Genetic polymorphisms associated with autoinflammatory diseases, methods of detection and uses thereof

ABSTRACT

The present invention provides compositions and methods based on genetic polymorphisms that are associated with autoinflammatory diseases such as psoriasis. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents for their detection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. non-provisionalapplication Ser. No. 12/494,800, filed Jun. 30, 2009, which is anon-provisional application of U.S. provisional application Ser. No.61/134,042, filed Jul. 2, 2008, the contents of each of which are herebyincorporated by reference in their entirety into this application.

FIELD OF THE INVENTION

The present invention is in the field of diagnosis and therapy ofautoinflammatory diseases, as well as drug response. In particular, thepresent invention relates to specific single nucleotide polymorphisms(SNPs) in the human genome, and their association with psoriasis andrelated pathologies. The SNPs disclosed herein can be used as targetsfor the design of diagnostic reagents and the development of therapeuticagents, as well as for disease association and linkage analysis. Inparticular, the SNPs of the present invention are useful for such usesas identifying an individual who has an increased or decreased risk ofdeveloping psoriasis, for early detection of the disease, for providingclinically important information for the prevention and/or treatment ofpsoriasis, for predicting progression or recurrence of psoriasis, forpredicting the seriousness or consequences of psoriasis in anindividual, for determining the prognosis of an individual's recoveryfrom psoriasis, for screening and selecting therapeutic agents, and forpredicting a patient's response to therapeutic agents (such asevaluating the likelihood of an individual responding positively to aparticular therapeutic agent), particularly for the treatment orprevention of psoriasis. The SNPs disclosed herein are also useful forhuman identification applications. Methods, assays, kits, and reagentsfor detecting the presence of these polymorphisms and their encodedproducts are provided.

BACKGROUND OF THE INVENTION

Examples of autoinflammatory diseases include inflammatory andautoimmune disorders such as psoriasis, inflammatory bowel disease (IBD)(including Crohn's disease, which further includes both adult andpediatric Crohn's disease, and ulcerative colitis) and other chronicinflammatory disorders, atopic dermatitis, multiple sclerosis,rheumatoid arthritis (RA), ankylosing spondylitis (AS), celiac disease,Graves' disease (including Graves' ophthalmopathy (GO) and Graves'disease without opthalmopathy), and Barrett's esophagus.

Psoriasis is described here as an example of an autoinflammatorydisease.

Psoriasis

Psoriasis is a common, chronic, T-cell-mediated inflammatory disease ofthe skin affecting ˜2-3% of whites of European descent. Although thisdisease is found in all populations, its prevalence is lower in Asiansand African-Americans and also declines at lower latitudes. The mostcommon form, psoriasis vulgaris, is characterized by varying numbers ofred, raised, scaly skin patches that can be present on any body surface,but most often appear on the elbows, knees and scalp. The onset ofdisease usually occurs early in life (15-30 years) and affects males andfemales equally. Up to 30% of individuals with psoriasis will develop aninflammatory arthritis, which can affect the peripheral joints of thehands and feet, large joints, or the central axial-skeleton.Pathologically, psoriasis is characterized by vascular changes,hyperproliferation of keratinocytes, altered epidermal differentiationand inflammation. In particular, the reaction of cells in the epidermisto type 1 effector molecules produced by T-cells results in thecharacteristic pathology of the plaques.

The genetics of psoriasis are complex and highly heritable as evidencedby an increased rate of concordance in monozygotic twins over dizygotictwins (35%-72% vs. 12-23%) and a substantially increased incidence infamily members of affected individuals (first-degree relatives 6%);however, it is clear that environmental effects are also responsible fordisease susceptibility. Ten genome-wide linkage scans have resulted instrong evidence for a susceptibility locus in the MHC region on 6p21(PSORS 1 [MIM 177900]), but have not yielded consistent evidence forother regions.

Linkage and association in the MHC (6p21) are thought to be due toHLA-C, in particular psoriasis susceptibility effects are thought to becaused by the *0602 allele, although other candidate genes in the areamay also contribute to disease predisposition. Association studies haveidentified three genes under linkage peaks, with considerable evidencefor linkage disequilibrium with psoriasis, namely SLC9A3R1/NAT9 andRAPTOR (KIAA1303) in 17q25, and SLC12A8 in 3q21. Several other genesincluding VDR, MMP2, IL10, IL1RN, IL12B, and IRF2 (Genetic AssociationDatabase, OMIM) have been associated with psoriasis in sample sets ofvarying sizes and of different ethnicities; however, without more datafrom additional independent studies, it is difficult to drawstatistically sound conclusions about whether these markers are trulyassociated with disease. Thus, there remains a need for the discovery ofreliable markers that can associate themselves with psoriasis, and inturn, would facilitate the diagnosis and treatment of the disease.

The discovery of genetic markers which are useful in identifyingpsoriasis individuals who are at increased risk for developing psoriasismay lead to, for example, better therapeutic strategies, economicmodels, and health care policy decisions.

Single Nucleotide Polymorphisms (SNPs)

The genomes of all organisms undergo spontaneous mutation in the courseof their continuing evolution, generating variant forms of progenitorgenetic sequences. Gusella, Ann Rev Biochem 55:831-854 (1986). A variantform may confer an evolutionary advantage or disadvantage relative to aprogenitor form or may be neutral. In some instances, a variant formconfers an evolutionary advantage to the species and is eventuallyincorporated into the DNA of many or most members of the species andeffectively becomes the progenitor form. Additionally, the effects of avariant form may be both beneficial and detrimental, depending on thecircumstances. For example, a heterozygous sickle cell mutation confersresistance to malaria, but a homozygous sickle cell mutation is usuallylethal. In many cases, both progenitor and variant forms survive andco-exist in a species population. The coexistence of multiple forms of agenetic sequence gives rise to genetic polymorphisms, including SNPs.

Approximately 90% of all genetic polymorphisms in the human genome areSNPs. SNPs are single base positions in DNA at which different alleles,or alternative nucleotides, exist in a population. The SNP position(interchangeably referred to herein as SNP, SNP site, SNP locus, SNPmarker, or marker) is usually preceded by and followed by highlyconserved sequences of the allele (e.g., sequences that vary in lessthan 1/100 or 1/1000 members of the populations). An individual may behomozygous or heterozygous for an allele at each SNP position. A SNPcan, in some instances, be referred to as a “cSNP” to denote that thenucleotide sequence containing the SNP is an amino acid coding sequence.

A SNP may arise from a substitution of one nucleotide for another at thepolymorphic site. Substitutions can be transitions or transversions. Atransition is the replacement of one purine nucleotide by another purinenucleotide, or one pyrimidine by another pyrimidine. A transversion isthe replacement of a purine by a pyrimidine, or vice versa. A SNP mayalso be a single base insertion or deletion variant referred to as an“indel.” Weber et al., “Human diallelic insertion/deletionpolymorphisms,” Am J Hum Genet 71(4):854-62 (October 2002).

A synonymous codon change, or silent mutation/SNP (terms such as “SNP,”“polymorphism,” “mutation,” “mutant,” “variation,” and “variant” areused herein interchangeably), is one that does not result in a change ofamino acid due to the degeneracy of the genetic code. A substitutionthat changes a codon coding for one amino acid to a codon coding for adifferent amino acid (i.e., a non-synonymous codon change) is referredto as a missense mutation. A nonsense mutation results in a type ofnon-synonymous codon change in which a stop codon is formed, therebyleading to premature termination of a polypeptide chain and a truncatedprotein. A read-through mutation is another type of non-synonymous codonchange that causes the destruction of a stop codon, thereby resulting inan extended polypeptide product. While SNPs can be bi-, tri-, ortetra-allelic, the vast majority of the SNPs are bi-allelic, and arethus often referred to as “bi-allelic markers,” or “di-allelic markers.”

As used herein, references to SNPs and SNP genotypes include individualSNPs and/or haplotypes, which are groups of SNPs that are generallyinherited together. Haplotypes can have stronger correlations withdiseases or other phenotypic effects compared with individual SNPs, andtherefore may provide increased diagnostic accuracy in some cases.Stephens et al., Science 293:489-493 (July 2001).

Causative SNPs are those SNPs that produce alterations in geneexpression or in the expression, structure, and/or function of a geneproduct, and therefore are most predictive of a possible clinicalphenotype. One such class includes SNPs falling within regions of genesencoding a polypeptide product, i.e. cSNPs. These SNPs may result in analteration of the amino acid sequence of the polypeptide product (i.e.,non-synonymous codon changes) and give rise to the expression of adefective or other variant protein. Furthermore, in the case of nonsensemutations, a SNP may lead to premature termination of a polypeptideproduct. Such variant products can result in a pathological condition,e.g., genetic disease. Examples of genes in which a SNP within a codingsequence causes a genetic disease include sickle cell anemia and cysticfibrosis.

Causative SNPs do not necessarily have to occur in coding regions;causative SNPs can occur in, for example, any genetic region that canultimately affect the expression, structure, and/or activity of theprotein encoded by a nucleic acid. Such genetic regions include, forexample, those involved in transcription, such as SNPs in transcriptionfactor binding domains, SNPs in promoter regions, in areas involved intranscript processing, such as SNPs at intron-exon boundaries that maycause defective splicing, or SNPs in mRNA processing signal sequencessuch as polyadenylation signal regions. Some SNPs that are not causativeSNPs nevertheless are in close association with, and therefore segregatewith, a disease-causing sequence. In this situation, the presence of aSNP correlates with the presence of, or predisposition to, or anincreased risk in developing the disease. These SNPs, although notcausative, are nonetheless also useful for diagnostics, diseasepredisposition screening, and other uses.

An association study of a SNP and a specific disorder involvesdetermining the presence or frequency of the SNP allele in biologicalsamples from individuals with the disorder of interest, such aspsoriasis, and comparing the information to that of controls (i.e.,individuals who do not have the disorder; controls may be also referredto as “healthy” or “normal” individuals) who are preferably of similarage and race. The appropriate selection of patients and controls isimportant to the success of SNP association studies. Therefore, a poolof individuals with well-characterized phenotypes is extremelydesirable.

A SNP may be screened in diseased tissue samples or any biologicalsample obtained from a diseased individual, and compared to controlsamples, and selected for its increased (or decreased) occurrence in aspecific pathological condition, such as pathologies related topsoriasis. Once a statistically significant association is establishedbetween one or more SNP(s) and a pathological condition (or otherphenotype) of interest, then the region around the SNP can optionally bethoroughly screened to identify the causative genetic locus/sequence(s)(e.g., causative SNP/mutation, gene, regulatory region, etc.) thatinfluences the pathological condition or phenotype. Association studiesmay be conducted within the general population and are not limited tostudies performed on related individuals in affected families (linkagestudies).

Clinical trials have shown that patient response to treatment withpharmaceuticals is often heterogeneous. There is a continuing need toimprove pharmaceutical agent design and therapy. In that regard, SNPscan be used to identify patients most suited to therapy with particularpharmaceutical agents (this is often termed “pharmacogenomics”).Similarly, SNPs can be used to exclude patients from certain treatmentdue to the patient's increased likelihood of developing toxic sideeffects or their likelihood of not responding to the treatment.Pharmacogenomics can also be used in pharmaceutical research to assistthe drug development and selection process. Linder et al., ClinicalChemistry 43:254 (1997); Marshall, Nature Biotechnology 15:1249 (1997);International Patent Application WO 97/40462, Spectra Biomedical; andSchafer et al., Nature Biotechnology 16:3 (1998).

SUMMARY OF THE INVENTION

The present invention relates to the identification of SNPs, as well asunique combinations of such SNPs and haplotypes of SNPs, that areassociated with autoinflammatory diseases such as psoriasis,particularly an increased or decreased risk of developingautoinflammatory diseases and responsiveness to therapies used to treatautoinflammatory diseases. The polymorphisms disclosed herein aredirectly useful as targets for the design of diagnostic and prognosticreagents and the development of therapeutic and preventive agents foruse in the diagnosis, prognosis, treatment, and/or prevention ofpsoriasis, as well as for predicting a patient's response to therapeuticagents, particularly for the treatment or prevention of psoriasis.

Based on the identification of SNPs associated with psoriasis, thepresent invention also provides methods of detecting these variants aswell as the design and preparation of detection reagents needed toaccomplish this task. The invention specifically provides, for example,SNPs associated with psoriasis, isolated nucleic acid molecules(including DNA and RNA molecules) containing these SNPs, variantproteins encoded by nucleic acid molecules containing such SNPs,antibodies to the encoded variant proteins, computer-based and datastorage systems containing the novel SNP information, methods ofdetecting these SNPs in a test sample, methods of identifyingindividuals who have an altered (i.e., increased or decreased) risk ofdeveloping psoriasis, methods for determining the risk of an individualfor recurring psoriasis, methods for prognosing the severity orconsequences of psoriasis, methods of treating an individual who has anincreased risk for psoriasis, and methods for identifying individuals(e.g., determining a particular individual's likelihood) who have analtered (i.e., increased or decreased) likelihood of responding to adrug treatment, particularly drug treatment of psoriasis, based on thepresence or absence of one or more particular nucleotides (alleles) atone or more SNP sites disclosed herein or the detection of one or moreencoded variant products (e.g., variant mRNA transcripts or variantproteins), methods of identifying individuals who are more or lesslikely to respond to a treatment (or more or less likely to experienceundesirable side effects from a treatment), methods of screening forcompounds useful in the treatment or prevention of a disorder associatedwith a variant gene/protein, compounds identified by these methods,methods of treating or preventing disorders mediated by a variantgene/protein, methods of using the novel SNPs of the present inventionfor human identification, etc.

The present invention further provides methods for selecting orformulating a treatment regimen (e.g., methods for determining whetheror not to administer a drug treatment to an individual having psoriasis,or who is at risk for developing psoriasis in the future, or who haspreviously had psoriasis, methods for selecting a particular treatmentregimen such as dosage and frequency of administration of a drug, or aparticular form/type of a drug such as a particular pharmaceuticalformulation or compound, methods for administering an alternativetreatment to individuals who are predicted to be unlikely to respondpositively to a particular treatment, etc.), and methods for determiningthe likelihood of experiencing toxicity or other undesirable sideeffects from a drug treatment, etc. The present invention also providesmethods for selecting individuals to whom a therapeutic agent will beadministered based on the individual's genotype, and methods forselecting individuals for a clinical trial of a therapeutic agent basedon the genotypes of the individuals (e.g., selecting individuals toparticipate in the trial who are most likely to respond positively froma drug treatment and/or excluding individuals from the trial who areunlikely to respond positively from a drug treatment based on their SNPgenotype(s), or selecting individuals who are unlikely to respondpositively to a particular drug treatment based on their SNP genotype(s)to participate in a clinical trial of another type of drug that maybenefit them). The present invention further provides methods forreducing an individual's risk of developing psoriasis using a drugtreatment, including preventing recurring psoriasis using a drugtreatment, when said individual carries one or more SNP allelesidentified herein as being associated with psoriasis.

In Tables 1 and 2, the present invention provides gene information,references to the identification of transcript sequences (SEQ IDNOS:1-2), encoded amino acid sequences (SEQ ID NOS:3-4), genomicsequences (SEQ ID NOS:13-20), transcript-based context sequences (SEQ IDNOS:5-12) and genomic-based context sequences (SEQ ID NOS:21-307) thatcontain the SNPs of the present invention, and extensive SNP informationthat includes observed alleles, allele frequencies, populations/ethnicgroups in which alleles have been observed, information about the typeof SNP and corresponding functional effect, and, for cSNPs, informationabout the encoded polypeptide product. The actual transcript sequences(SEQ ID NOS:1-2), amino acid sequences (SEQ ID NOS:3-4), genomicsequences (SEQ ID NOS:13-20), transcript-based SNP context sequences(SEQ ID NOS:5-12), and genomic-based SNP context sequences (SEQ IDNOS:21-307), together with primer sequences (SEQ ID NOS:308-541) areprovided in the Sequence Listing.

In certain exemplary embodiments, the invention provides methods foridentifying an individual who has an altered risk for developingpsoriasis (including, for example, a first incidence and/or a recurrenceof the disease), in which the method comprises detecting a singlenucleotide polymorphism (SNP) in any one of the nucleotide sequences ofSEQ ID NOS:1-2, SEQ ID NOS:5-12, SEQ ID NOS:13-20, and SEQ ID NOS:21-307in said individual's nucleic acids, wherein the SNP is specified inTable 1 and/or Table 2, and the presence of the SNP is indicative of analtered risk for psoriasis in said individual. In certain exemplaryembodiments of the invention, SNPs that occur naturally in the humangenome are provided as isolated nucleic acid molecules. These SNPs areassociated with psoriasis such that they can have a variety of uses inthe diagnosis, prognosis, treatment, and/or prevention of psoriasis andrelated pathologies (e.g., Crohn's disease and other autoinflammatorydiseases). In an alternative embodiment, a nucleic acid of the inventionis an amplified polynucleotide, which is produced by amplification of aSNP-containing nucleic acid template. In another embodiment, theinvention provides for a variant protein that is encoded by a nucleicacid molecule containing a SNP disclosed herein.

In yet another embodiment of the invention, a reagent for detecting aSNP in the context of its naturally-occurring flanking nucleotidesequences (which can be, e.g., either DNA or mRNA) is provided. Inparticular, such a reagent may be in the form of, for example, ahybridization probe or an amplification primer that is useful in thespecific detection of a SNP of interest. In an alternative embodiment, aprotein detection reagent is used to detect a variant protein that isencoded by a nucleic acid molecule containing a SNP disclosed herein. Apreferred embodiment of a protein detection reagent is an antibody or anantigen-reactive antibody fragment.

Various embodiments of the invention also provide kits comprising SNPdetection reagents, and methods for detecting the SNPs disclosed hereinby employing detection reagents. In a specific embodiment, the presentinvention provides for a method of identifying an individual having anincreased or decreased risk of developing psoriasis by detecting thepresence or absence of one or more SNP alleles disclosed herein. Inanother embodiment, a method for diagnosis of psoriasis by detecting thepresence or absence of one or more SNP alleles disclosed herein isprovided. The present invention also provides methods for evaluatingwhether an individual is likely (or unlikely) to respond to a drugtreatment, particularly treatment of psoriasis, by detecting thepresence or absence of one or more SNP alleles disclosed herein.

For example, the SNP allele can be an allele of an IL12B region SNPselected from the group consisting of rs2546892, rs1433048, rs6894567,rs17860508, rs7709212, rs953861, rs6869411, rs1833754, rs6861600,rs1368437, rs2082412, rs7730390, rs3181225, rs1368439, rs3212227,rs3213120, rs3213119, and rs2853696 (see Tables 9-10), and the SNPsprovided in Table 11 (e.g., rs1422878), or a combination of any numberof these. Exemplary combinations include combinations consisting of,consisting essentially of, and comprising the nine IL12B region SNPsrs2546892, rs1433048, rs6894567, rs17860508, rs7709212, rs953861,rs6869411, rs1833754, and rs6861600 (see Table 9) and combinationsconsisting of, consisting essentially of, and comprising the nine IL12Bregion SNPs rs1368437, rs2082412, rs7730390, rs3181225, rs1368439,rs3212227, rs3213120, rs3213119, and rs2853696 (see Table 10). These andother combinations can further include one or more SNPs provided inTable 11 (e.g., rs1422878).

Further, the SNP allele can be an allele of an IL23R region SNP selectedfrom the group consisting of rs7530511, rs10489629, rs4655692,rs2201841, rs11465804, rs10489628, rs1343152, rs10789229, rs10889671,rs11209026, rs10889674, rs12085634, rs1343151, rs1008193, rs6693831,rs10889675, rs11465827, rs10889677, rs4655531, rs11209030, rs1857292,rs11209031, and rs11209032 (see Table 7), including combinationsconsisting of, consisting essentially of, and comprising any of these 23SNPs. Exemplary combinations include combinations consisting of,consisting essentially of, and comprising the five IL23R region SNPsrs7530511, rs11465804, rs10889671, rs11209026, and rs1857292 (see Table5), combinations consisting of, consisting essentially of, andcomprising the three IL23R region SNPs rs7530511, rs10889671, andrs11209026 (see Table 6), and combinations consisting of, consistingessentially of, and comprising the twelve IL23R region SNPs rs2201841,rs10489628, 10889674, rs12085634, rs1008193, rs10889675, rs11465827,rs10889677, rs4655531, rs11209030, rs11209031, and rs11209032 (see Table8).

In certain exemplary embodiments, the invention provides haplotypesconsisting of, consisting essentially of, and comprising the nine IL12Bregion SNPs rs2546892, rs1433048, rs6894567, rs17860508, rs7709212,rs953861, rs6869411, rs1833754, and rs6861600 (see Table 9), as well aseach of these SNPs individually, any combination of any of these SNPs,and compositions and methods based on these SNP haplotypes, combinationsof SNPs, and individual SNPs, particularly methods related to psoriasisor related pathologies (e.g., Crohn's disease).

In further exemplary embodiments, the invention provides haplotypesconsisting of, consisting essentially of, and comprising the nine IL12Bregion SNPs rs1368437, rs2082412, rs7730390, rs3181225, rs1368439,rs3212227, rs3213120, rs3213119, and rs2853696 (see Table 10), as wellas each of these SNPs individually, any combination of any of theseSNPs, and compositions and methods based on these SNP haplotypes,combinations of SNPs, and individual SNPs, particularly methods relatedto psoriasis or related pathologies (e.g., Crohn's disease).

In further exemplary embodiments, the invention provides any of the SNPsin Table 11, including each of these SNPs individually as well as anycombination of any of these SNPs, and compositions and methods based onthese SNPs in Table 11 (including any of the SNPs individually as wellas combinations thereof), particularly methods related to psoriasis orrelated pathologies (e.g., Crohn's disease). In certain embodiments, theSNP(s) include at least one of rs1422878, rs6861600, and/or rs3212227.

In further exemplary embodiments, the invention provides haplotypesconsisting of, consisting essentially of, and comprising the 23 IL23Rregion SNPs rs7530511, rs10489629, rs4655692, rs2201841, rs11465804,rs10489628, rs1343152, rs10789229, rs10889671, rs11209026, rs10889674,rs12085634, rs1343151, rs1008193, rs6693831, rs10889675, rs11465827,rs10889677, rs4655531, rs11209030, rs1857292, rs11209031, and rs11209032(Table 7) (as well as haplotypes consisting of, consisting essentiallyof, and comprising the twelve IL23R region SNPs rs2201841, rs10489628,10889674, rs12085634, rs1008193, rs10889675, rs11465827, rs10889677,rs4655531, rs11209030, rs11209031, and rs11209032 (Table 8); haplotypesconsisting of, consisting essentially of, and comprising the five IL23Rregion SNPs rs7530511, rs11465804, rs10889671, rs11209026, and rs1857292(Table 5); and haplotypes consisting of, consisting essentially of, andcomprising the three IL23R region SNPs rs7530511, rs10889671, andrs11209026 (Table 6), as well as each of these SNPs individually, anycombination of any of these SNPs, and compositions and methods based onthese SNP haplotypes, combinations of SNPs, and individual SNPs,particularly methods related to psoriasis or related pathologies (e.g.,Crohn's disease).

In further exemplary embodiments, the invention provides methods fordiagnosis of psoriasis and related pathologies by detecting one or moreSNPs or SNP haplotypes disclosed herein, including, for example,detecting the presence or absence of any of the alleles of any of theSNPs that make up the haplotypes disclosed herein. In further exemplaryembodiments, the invention provides methods for identifying anindividual having an altered (either increased or decreased) risk fordeveloping psoriasis and related pathologies by detecting one or moreSNPs or SNP haplotypes disclosed herein, including, for example,detecting the presence or absence of any of the alleles of any of theSNPs that make up the haplotypes disclosed herein. Thus, methods areprovided for determining an individual's risk for developing psoriasisand related pathologies, among other uses, using the SNPs and SNPhaplotypes disclosed herein (including any combination of any of theseSNPs, as well as any of these SNPs in combination with otherpolymorphisms).

Certain exemplary haplotypes of the invention consist of, consistessentially of, or comprise the IL12B region SNP allele combination ofrs2546892 (G), rs1433048 (A), rs6894567 (G), rs17860508 (C), rs7709212(C), rs953861 (A), rs6869411 (T), rs1833754 (T), and rs6861600 (G),particularly as non-risk haplotypes (which may be interchangeablyreferred to herein as “protective” haplotypes), as shown in Table 9.Certain other exemplary haplotypes of the invention consist of, consistessentially of, or comprise the IL12B region SNP allele combination ofrs1368437 (C), rs2082412 (A), rs7730390 (C), rs3181225 (G), rs1368439(T), rs3212227 (G), rs3213120 (C), rs3213119 (G), and rs2853696 (C),particularly as non-risk (protective) haplotypes, as shown in Table 10.

Certain other exemplary haplotypes of the invention consist of, consistessentially of, or comprise any of the following two combinations ofIL12B region SNP alleles, particularly as risk haplotypes (which may beinterchangeably referred to herein as a “susceptibility” haplotypes), asshown in Table 10:

1) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439(G), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (T); and

2) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439(T), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (C).

Other exemplary haplotypes of the invention consist of, consistessentially of, or comprise any of the following three combinations ofIL12B region SNP alleles, as shown in Table 10:

1) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439(T), rs3212227 (T), rs3213120 (T), rs3213119 (T), and rs2853696 (C);

2) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225 (A), rs1368439(T), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (C); and

3) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439(T), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (C).

Certain other exemplary haplotypes of the invention consist of, consistessentially of, or comprise the IL23R region SNP allele combination ofrs7530511 (T), rs11465804 (T), rs10889671 (A), rs11209026 (G), andrs1857292 (T), particularly as non-risk (protective) haplotypes, asshown in Table 5. Certain other exemplary haplotypes of the inventionconsist of, consist essentially of, or comprise the IL23R region SNPallele combination of rs7530511 (C), rs11465804 (G), rs10889671 (G),rs11209026 (A), and rs1857292 (A), particularly as non-risk (protective)haplotypes, as shown in Table 5. Certain other exemplary haplotypes ofthe invention consist of, consist essentially of, or comprise the IL23Rregion SNP allele combination of rs7530511 (C), rs11465804 (T),rs10889671 (G), rs11209026 (G), and rs1857292 (A), particularly as risk(susceptibility) haplotypes, as shown in Table 5. Certain otherexemplary haplotypes of the invention consist of, consist essentiallyof, or comprise any of the IL23R region SNP allele combinations shown inTable 5.

Certain other exemplary haplotypes of the invention consist of, consistessentially of, or comprise the IL23R region SNP allele combination ofrs7530511 (T), rs10889671 (A), and rs11209026 (G), particularly asnon-risk (protective) haplotypes, as shown in Table 6. Certain otherexemplary haplotypes of the invention consist of, consist essentiallyof, or comprise the IL23R region SNP allele combination of rs7530511(C), rs10889671 (G), and rs11209026 (A), particularly as non-risk(protective) haplotypes, as shown in Table 6. Certain other exemplaryhaplotypes of the invention consist of, consist essentially of, orcomprise the IL23R region SNP allele combination of rs7530511 (C),rs10889671 (G), and rs11209026 (G), particularly as risk(susceptibility) haplotypes, as shown in Table 6.

Certain other exemplary haplotypes of the invention consist of, consistessentially of, or comprise the IL23R region SNP allele combination ofrs7530511 (T), rs10489629 (T), rs4655692 (A), rs2201841 (A), rs11465804(T), rs10489628 (G), rs1343152 (A), rs10789229 (C), rs10889671 (A),rs11209026 (G), rs10889674 (T), rs12085634 (T), rs1343151 (G), rs1008193(C), rs6693831 (T), rs10889675 (C), rs11465827 (T), rs10889677 (C),rs4655531 (C), rs11209030 (C), rs1857292 (T), rs11209031 (A), andrs11209032 (G), particularly as non-risk (protective) haplotypes, asshown in Table 7. Certain other exemplary haplotypes of the inventionconsist of, consist essentially of, or comprise the IL23R region SNPallele combination of rs7530511 (C), rs10489629 (C), rs4655692 (G),rs2201841 (A), rs11465804 (G), rs10489628 (G), rs1343152 (C), rs10789229(T), rs10889671 (G), rs11209026 (A), rs10889674 (T), rs12085634 (T),rs1343151 (A), rs1008193 (C), rs6693831 (C), rs10889675 (C), rs11465827(T), rs10889677 (C), rs4655531 (C), rs11209030 (C), rs1857292 (A),rs11209031 (A), and rs11209032 (G), particularly as non-risk(protective) haplotypes, as shown in Table 7. Certain other exemplaryhaplotypes of the invention consist of, consist essentially of, orcomprise any of the IL23R region SNP allele combinations shown in Table7.

Certain other exemplary haplotypes of the invention consist of, consistessentially of, or comprise the IL23R region SNP allele combination ofrs2201841 (A), rs10489628 (G), 10889674 (T), rs12085634 (T), rs1008193(C), rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531 (C),rs11209030 (C), rs11209031 (A), and rs11209032 (G), particularly asnon-risk (protective) haplotypes, as shown in Table 8. Certain otherexemplary haplotypes of the invention consist of, consist essentiallyof, or comprise the IL23R region SNP allele combination of rs2201841(G), rs10489628 (G), 10889674 (G), rs12085634 (T), rs1008193 (C),rs10889675 (C), rs11465827 (T), rs10889677 (A), rs4655531 (C),rs11209030 (C), rs11209031 (A), and rs11209032 (A), particularly as risk(susceptibility) haplotypes, as shown in Table 8. Certain otherexemplary haplotypes of the invention consist of, consist essentiallyof, or comprise the IL23R region SNP allele combination of rs2201841(A), rs10489628 (G), 10889674 (G), rs12085634 (A), rs1008193 (C),rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531 (C),rs11209030 (C), rs11209031 (A), and rs11209032 (G), particularly as risk(susceptibility) haplotypes, as shown in Table 8. Certain otherexemplary haplotypes of the invention consist of, consist essentiallyof, or comprise any of the IL23R region SNP allele combinations shown inTable 8.

Furthermore, certain exemplary embodiments of the invention providemethods for identifying an individual having an increased risk ofdeveloping psoriasis by detecting one or more haplotypes, particularlyan IL12B region haplotype selected from the group consisting of thefollowing two risk haplotypes:

1) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439(G), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (T) (seeTable 10); and

2) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439(T), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (C) (seeTable 10).

Alternative exemplary embodiment of the invention provide methods foridentifying individuals having a decreased risk of developing psoriasis(particularly as compared to the risk of developing psoriasis for theIL12B risk haplotypes above) by detecting one or more haplotypes,particularly an IL12B region haplotype selected from the groupconsisting of the following two non-risk (protective) haplotypes:

1) rs2546892 (G), rs1433048 (A), rs6894567 (G), rs17860508 (C),rs7709212 (C), rs953861 (A), rs6869411 (T), rs1833754 (T), and rs6861600(G) (see Table 9); and

2) rs1368437 (C), rs2082412 (A), rs7730390 (C), rs3181225 (G), rs1368439(T), rs3212227 (G), rs3213120 (C), rs3213119 (G), and rs2853696 (C) (seeTable 10).

Alternative exemplary embodiment of the invention provide methods foridentifying individuals having an increased risk of developing psoriasisby detecting one or more haplotypes, particularly an IL23R regionhaplotype selected from the group consisting of the following four risk(susceptibility) haplotypes:

1) rs7530511 (C), rs11465804 (T), rs10889671 (G), rs11209026 (G), andrs1857292 (A) (see Table 5);

2) rs7530511 (C), rs10889671 (G), and rs11209026 (G) (see Table 6);

3) rs2201841 (G), rs10489628 (G), 10889674 (G), rs12085634 (T),rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (A), rs4655531(C), rs11209030 (C), rs11209031 (A), and rs11209032 (A) (see Table 8);and

4) rs2201841 (A), rs10489628 (G), 10889674 (G), rs12085634 (A),rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531(C), rs11209030 (C), rs11209031 (A), and rs11209032 (G) (see Table 8).

Alternative exemplary embodiment of the invention provide methods foridentifying individuals having a decreased risk of developing psoriasis(particularly as compared to the risk of developing psoriasis for theIL23R risk haplotypes above) by detecting one or more haplotypes,particularly an IL23R region haplotype selected from the groupconsisting of the following seven non-risk (protective) haplotypes:

1) rs7530511 (T), rs11465804 (T), rs10889671 (A), rs11209026 (G), andrs1857292 (T) (see Table 5)

2) rs7530511 (C), rs11465804 (G), rs10889671 (G), rs11209026 (A), andrs1857292 (A) (see Table 5)

3) rs7530511 (T), rs10889671 (A), and rs11209026 (G) (see Table 6)

4) rs7530511 (C), rs10889671 (G), and rs11209026 (A) (see Table 6)

5) rs7530511 (T), rs10489629 (T), rs4655692 (A), rs2201841 (A),rs11465804 (T), rs10489628 (G), rs1343152 (A), rs10789229 (C),rs10889671 (A), rs11209026 (G), rs10889674 (T), rs12085634 (T),rs1343151 (G), rs1008193 (C), rs6693831 (T), rs10889675 (C), rs11465827(T), rs10889677 (C), rs4655531 (C), rs11209030 (C), rs1857292 (T),rs11209031 (A), and rs11209032 (G) (see Table 7)

6) rs7530511 (C), rs10489629 (C), rs4655692 (G), rs2201841 (A),rs11465804 (G), rs10489628 (G), rs1343152 (C), rs10789229 (T),rs10889671 (G), rs11209026 (A), rs10889674 (T), rs12085634 (T),rs1343151 (A), rs1008193 (C), rs6693831 (C), rs10889675 (C), rs11465827(T), rs10889677 (C), rs4655531 (C), rs11209030 (C), rs1857292 (A),rs11209031 (A), and rs11209032 (G) (see Table 7); and

7) rs2201841 (A), rs10489628 (G), 10889674 (T), rs12085634 (T),rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531(C), rs11209030 (C), rs11209031 (A), and rs11209032 (G) (see Table 8).

The SNPs and haplotypes provided herein can be combined with othergenetic variants, such as to increase the power to determine psoriasisrisk. For example, the SNPs and haplotypes provided herein can becombined with any of the SNPs and haplotypes disclosed in U.S. patentapplication Ser. No. 11/899,017, filed Aug. 31, 2007 (Begovich et al.),and Cargill et al., “A large-scale genetic association study confirmsIL12B and leads to the identification of IL23R as psoriasis risk genes”,Am J Hum Genet. 2007 February; 80(2):273-90, both of which areincorporated herein by reference in their entirety.

The nucleic acid molecules of the invention can be inserted in anexpression vector, such as to produce a variant protein in a host cell.Thus, the present invention also provides for a vector comprising aSNP-containing nucleic acid molecule, genetically-engineered host cellscontaining the vector, and methods for expressing a recombinant variantprotein using such host cells. In another specific embodiment, the hostcells, SNP-containing nucleic acid molecules, and/or variant proteinscan be used as targets in a method for screening and identifyingtherapeutic agents or pharmaceutical compounds useful in the treatmentor prevention of psoriasis.

An aspect of this invention is a method for treating or preventingpsoriasis (including, for example, a first occurrence and/or arecurrence of the disease), in a human subject wherein said humansubject harbors a SNP, gene, transcript, and/or encoded proteinidentified in Tables 1 and 2, which method comprises administering tosaid human subject a therapeutically or prophylactically effectiveamount of one or more agents counteracting the effects of the disease,such as by inhibiting (or stimulating) the activity of a gene,transcript, and/or encoded protein identified in Tables 1 and 2.

Another aspect of this invention is a method for identifying an agentuseful in therapeutically or prophylactically treating psoriasis, in ahuman subject wherein said human subject harbors a SNP, gene,transcript, and/or encoded protein identified in Tables 1 and 2, whichmethod comprises contacting the gene, transcript, or encoded proteinwith a candidate agent under conditions suitable to allow formation of abinding complex between the gene, transcript, or encoded protein and thecandidate agent and detecting the formation of the binding complex,wherein the presence of the complex identifies said agent.

Another aspect of this invention is a method for treating or preventingpsoriasis in a human subject, in which the method comprises:

(i) determining that said human subject harbors a SNP, gene, transcript,and/or encoded protein identified in Tables 1 and 2, and

(ii) administering to said subject a therapeutically or prophylacticallyeffective amount of one or more agents counteracting the effects of thedisease.

Another aspect of the invention is a method for identifying a human whois likely to benefit from a drug treatment, in which the methodcomprises detecting an allele of one or more SNPs disclosed herein insaid human's nucleic acids, wherein the presence of the allele indicatesthat said human is likely to benefit from the drug treatment.

Another aspect of the invention is a method for identifying a human whois likely to benefit from a drug treatment, in which the methodcomprises detecting an allele of one or more SNPs that are in LD withone or more SNPs disclosed herein in said human's nucleic acids, whereinthe presence of the allele of the LD SNP indicates that said human islikely to benefit from the drug treatment.

Many other uses and advantages of the present invention will be apparentto those skilled in the art upon review of the detailed description ofthe preferred embodiments herein. Solely for clarity of discussion, theinvention is described in the sections below by way of non-limitingexamples.

Description of the Text (ASCII) File Submitted Electronically ViaEFS-Web

The following text (ASCII) file is submitted electronically via EFS-Webas part of the instant application:

File CD000025ORD_SEQLIST.txt provides the Sequence Listing. The SequenceListing provides the transcript sequences (SEQ ID NOS:1-2) and proteinsequences (SEQ ID NOS:3-4) as referred to in Table 1, and genomicsequences (SEQ ID NOS:13-20) as referred to in Table 2, for eachpsoriasis-associated gene (or genomic region for intergenic SNPs) thatcontains one or more SNPs of the present invention. Also provided in theSequence Listing are context sequences flanking each SNP, including bothtranscript-based context sequences as referred to in Table 1 (SEQ IDNOS:5-12) and genomic-based context sequences as referred to in Table 2(SEQ ID NOS:21-307). In addition, the Sequence Listing provides theprimer sequences from Table 3 (SEQ ID NOS:308-541), which areoligonucleotides that have been synthesized and used in the laboratoryto assay certain SNPs disclosed herein by allele-specific PCR during thecourse of association studies to verify the association of these SNPswith psoriasis. The context sequences generally provide 100 bp upstream(5′) and 100 bp downstream (3′) of each SNP, with the SNP in the middleof the context sequence, for a total of 200 bp of context sequencesurrounding each SNP.

File CD000025ORD_SEQLIST.txt is 978 KB in size, and was created on Jun.23, 2009.

This text file is hereby incorporated by reference pursuant to 37 CFR1.77(b)(4).

Description of Table 1 and Table 2

Table 1 and Table 2 (both provided below) disclose the SNP andassociated gene/transcript/protein information of the present invention.For each gene, Table 1 provides a header containing gene, transcript andprotein information, followed by a transcript and protein sequenceidentifier (SEQ ID NO), and then SNP information regarding each SNPfound in that gene/transcript including the transcript context sequence.For each gene in Table 2, a header is provided that contains gene andgenomic information, followed by a genomic sequence identifier (SEQ IDNO) and then SNP information regarding each SNP found in that gene,including the genomic context sequence.

Note that SNP markers may be included in both Table 1 and Table 2; Table1 presents the SNPs relative to their transcript sequences and encodedprotein sequences, whereas Table 2 presents the SNPs relative to theirgenomic sequences. In some instances Table 2 may also include, after thelast gene sequence, genomic sequences of one or more intergenic regions,as well as SNP context sequences and other SNP information for any SNPsthat lie within these intergenic regions. Additionally, in either Table1 or 2 a “Related Interrogated SNP” may be listed following a SNP whichis determined to be in LD with that interrogated SNP according to thegiven Power value. SNPs can be readily cross-referenced between allTables based on their Celera hCV (or, in some instances, hDV)identification numbers and/or public rs identification numbers, and tothe Sequence Listing based on their corresponding SEQ ID NOs.

The gene/transcript/protein information includes:

-   -   a gene number (1 through n, where n=the total number of genes in        the Table),    -   a gene symbol, along with an Entrez gene identification number        (Entrez Gene database, National Center for Biotechnology        Information (NCBI), National Library of Medicine, National        Institutes of Health)    -   a gene name,    -   an accession number for the transcript (e.g., RefSeq NM number,        or a Celera hCT identification number if no RefSeq NM number is        available) (Table 1 only),    -   an accession number for the protein (e.g., RefSeq NP number, or        a Celera hCP identification number if no RefSeq NP number is        available) (Table 1 only),    -   the chromosome number of the chromosome on which the gene is        located,    -   an OMIM (“Online Mendelian Inheritance in Man” database, Johns        Hopkins University/NCBI) public reference number for the gene,        and OMIM information such as alternative gene/protein name(s)        and/or symbol(s) in the OMIM entry.

Note that, due to the presence of alternative splice forms, multipletranscript/protein entries may be provided for a single gene entry inTable 1; i.e., for a single Gene Number, multiple entries may beprovided in series that differ in their transcript/protein informationand sequences.

Following the gene/transcript/protein information is a transcriptcontext sequence (Table 1), or a genomic context sequence (Table 2), foreach SNP within that gene.

After the last gene sequence, Table 2 may include additional genomicsequences of intergenic regions (in such instances, these sequences areidentified as “Intergenic region:” followed by a numericalidentification number), as well as SNP context sequences and other SNPinformation for any SNPs that lie within each intergenic region (suchSNPs are identified as “INTERGENIC” for SNP type).

Note that the transcript, protein, and transcript-based SNP contextsequences are all provided in the Sequence Listing. The transcript-basedSNP context sequences are provided in both Table 1 and also in theSequence Listing. The genomic and genomic-based SNP context sequencesare provided in the Sequence Listing. The genomic-based SNP contextsequences are provided in both Table 2 and in the Sequence Listing. SEQID NOs are indicated in Table 1 for the transcript-based contextsequences (SEQ ID NOS:5-12); SEQ ID NOs are indicated in Table 2 for thegenomic-based context sequences (SEQ ID NOS:21-307).

The SNP information includes:

-   -   Context sequence (taken from the transcript sequence in Table 1,        the genomic sequence in Table 2) with the SNP represented by its        IUB code, including 100 bp upstream (5′) of the SNP position        plus 100 bp downstream (3′) of the SNP position (the        transcript-based SNP context sequences in Table 1 are provided        in the Sequence Listing as SEQ ID NOS:5-12; the genomic-based        SNP context sequences in Table 2 are provided in the Sequence        Listing as SEQ ID NOS:21-307).    -   Celera hCV internal identification number for the SNP (in some        instances, an “hDV” number is given instead of an “hCV” number).    -   The corresponding public identification number for the SNP, the        rs number.    -   “SNP Chromosome Position” indicates the nucleotide position of        the SNP along the entire sequence of the chromosome as provided        in NCBI Genome Build 36.    -   SNP position (nucleotide position of the SNP within the given        transcript sequence (Table 1) or within the given genomic        sequence (Table 2)).    -   “Related Interrogated SNP” is the interrogated SNP with which        the listed SNP is in LD at the given value of Power.    -   SNP source (may include any combination of one or more of the        following five codes, depending on which internal sequencing        projects and/or public databases the SNP has been observed in:        “Applera”=SNP observed during the re-sequencing of genes and        regulatory regions of 39 individuals, “Celera”=SNP observed        during shotgun sequencing and assembly of the Celera human        genome sequence, “Celera Diagnostics”=SNP observed during        re-sequencing of nucleic acid samples from individuals who have        a disease, “dbSNP”=SNP observed in the dbSNP public database,        “HGBASE”=SNP observed in the HGBASE public database, “HGMD”=SNP        observed in the Human Gene Mutation Database (HGMD) public        database, “HapMap”=SNP observed in the International HapMap        Project public database, “CSNP”=SNP observed in an internal        Applied Biosystems (Foster City, Calif.) database of coding SNPS        (cSNPs).

Note that multiple “Applera” source entries for a single SNP indicatethat the same SNP was covered by multiple overlapping amplificationproducts and the re-sequencing results (e.g., observed allele counts)from each of these amplification products is being provided.

-   -   Population/allele/allele count information in the format of        [population1(first_allele,count|second_allele,count)population2(first_allele,count|second_allele,count)        total (first_allele,total count|second_allele,total count)]. The        information in this field includes populations/ethnic groups in        which particular SNP alleles have been observed        (“cau”=Caucasian, “his”=Hispanic, “chn”=Chinese, and        “afr”=African-American, “jpn”=Japanese, “ind”=Indian,        “mex”=Mexican, “ain”=“American Indian, “cra”=Celera donor,        “no_pop”=no population information available), identified SNP        alleles, and observed allele counts (within each population        group and total allele counts), where available [“-” in the        allele field represents a deletion allele of an        insertion/deletion (“indel”) polymorphism (in which case the        corresponding insertion allele, which may be comprised of one or        more nucleotides, is indicated in the allele field on the        opposite side of the “|”); “-” in the count field indicates that        allele count information is not available]. For certain SNPs        from the public dbSNP database, population/ethnic information is        indicated as follows (this population information is publicly        available in dbSNP): “HISP1”=human individual DNA (anonymized        samples) from 23 individuals of self-described HISPANIC        heritage; “PAC1”=human individual DNA (anonymized samples) from        24 individuals of self-described PACIFIC RIM heritage;        “CAUC1”=human individual DNA (anonymized samples) from 31        individuals of self-described CAUCASIAN heritage; “AFR1”=human        individual DNA (anonymized samples) from 24 individuals of        self-described AFRICAN/AFRICAN AMERICAN heritage; “P1”=human        individual DNA (anonymized samples) from 102 individuals of        self-described heritage; “PA130299515”; “SC_(—)12_A”=SANGER 12        DNAs of Asian origin from Corielle cell repositories, 6 of which        are male and 6 female; “SC_(—)12_C”=SANGER 12 DNAs of Caucasian        origin from Corielle cell repositories from the CEPH/UTAH        library, six male and six female; “SC_(—)12_AA”=SANGER 12 DNAs        of African-American origin from Corielle cell repositories 6 of        which are male and 6 female; “SC_(—)95_C”=SANGER 95 DNAs of        Caucasian origin from Corielle cell repositories from the        CEPH/UTAH library; and “SC_(—)12_CA”=Caucasians—12 DNAs from        Corielle cell repositories that are from the CEPH/UTAH library,        six male and six female.

Note that for SNPs of “Applera” SNP source, genes/regulatory regions of39 individuals (20 Caucasians and 19 African Americans) werere-sequenced and, since each SNP position is represented by twochromosomes in each individual (with the exception of SNPs on X and Ychromosomes in males, for which each SNP position is represented by asingle chromosome), up to 78 chromosomes were genotyped for each SNPposition. Thus, the sum of the African-American (“afr”) allele counts isup to 38, the sum of the Caucasian allele counts (“cau”) is up to 40,and the total sum of all allele counts is up to 78.

Note that semicolons separate population/allele/count informationcorresponding to each indicated SNP source; i.e., if four SNP sourcesare indicated, such as “Celera,” “dbSNP,” “HGBASE,” and “HGMD,” thenpopulation/allele/count information is provided in four groups which areseparated by semicolons and listed in the same order as the listing ofSNP sources, with each population/allele/count information groupcorresponding to the respective SNP source based on order; thus, in thisexample, the first population/allele/count information group wouldcorrespond to the first listed SNP source (Celera) and the thirdpopulation/allele/count information group separated by semicolons wouldcorrespond to the third listed SNP source (HGBASE); ifpopulation/allele/count information is not available for any particularSNP source, then a pair of semicolons is still inserted as aplace-holder in order to maintain correspondence between the list of SNPsources and the corresponding listing of population/allele/countinformation.

-   -   SNP type (e.g., location within gene/transcript and/or predicted        functional effect) [“MIS-SENSE MUTATION”=SNP causes a change in        the encoded amino acid (i.e., a non-synonymous coding SNP);        “SILENT MUTATION”=SNP does not cause a change in the encoded        amino acid (i.e., a synonymous coding SNP); “STOP CODON        MUTATION”=SNP is located in a stop codon; “NONSENSE        MUTATION”=SNP creates or destroys a stop codon; “UTR 5”=SNP is        located in a 5′ UTR of a transcript; “UTR 3”=SNP is located in a        3′ UTR of a transcript; “PUTATIVE UTR 5”=SNP is located in a        putative 5′ UTR; “PUTATIVE UTR 3”=SNP is located in a putative        3′ UTR; “DONOR SPLICE SITE”=SNP is located in a donor splice        site (5′ intron boundary); “ACCEPTOR SPLICE SITE”=SNP is located        in an acceptor splice site (3′ intron boundary); “CODING        REGION”=SNP is located in a protein-coding region of the        transcript; “EXON”=SNP is located in an exon; “INTRON”=SNP is        located in an intron; “hmCS”=SNP is located in a human-mouse        conserved segment; “TFBS”=SNP is located in a transcription        factor binding site; “UNKNOWN”=SNP type is not defined;        “INTERGENIC”=SNP is intergenic, i.e., outside of any gene        boundary].    -   Protein coding information (Table 1 only), where relevant, in        the format of [protein SEQ ID NO, amino acid position, (amino        acid-1, codon1) (amino acid-2, codon2)]. The information in this        field includes SEQ ID NO of the encoded protein sequence,        position of the amino acid residue within the protein identified        by the SEQ ID NO that is encoded by the codon containing the        SNP, amino acids (represented by one-letter amino acid codes)        that are encoded by the alternative SNP alleles (in the case of        stop codons, “X” is used for the one-letter amino acid code),        and alternative codons containing the alternative SNP        nucleotides which encode the amino acid residues (thus, for        example, for missense mutation-type SNPs, at least two different        amino acids and at least two different codons are generally        indicated; for silent mutation-type SNPs, one amino acid and at        least two different codons are generally indicated, etc.). In        instances where the SNP is located outside of a protein-coding        region (e.g., in a UTR region), “None” is indicated following        the protein SEQ ID NO.

Description of Table 3

Table 3 provides sequences (SEQ ID NOS:308-541) of primers that may beused to assay the SNPs disclosed herein by allele-specific PCR or othermethods, such as for uses related to psoriasis and otherautoinflammatory diseases.

Table 3 provides the following:

-   -   the column labeled “Marker” provides an hCV identification        number for each SNP that can be detected using the corresponding        primers.    -   the column labeled “Alleles” designates the two alternative        alleles (i.e., nucleotides) at the SNP site. These alleles are        targeted by the allele-specific primers (the allele-specific        primers are shown as Primer 1 and Primer 2). Note that alleles        may be presented in Table 3 based on a different orientation        (i.e., the reverse complement) relative to how the same alleles        are presented in Tables 1-2.    -   the column labeled “Primer 1 (Allele-Specific Primer)” provides        an allele-specific primer that is specific for an allele        designated in the “Alleles” column.    -   the column labeled “Primer 2 (Allele-Specific Primer)” provides        an allele-specific primer that is specific for the other allele        designated in the “Alleles” column.    -   the column labeled “Common Primer” provides a common primer that        is used in conjunction with each of the allele-specific primers        (i.e., Primer 1 and Primer 2) and which hybridizes at a site        away from the SNP position.

All primer sequences are given in the 5′ to 3′ direction.

Each of the nucleotides designated in the “Alleles” column matches or isthe reverse complement of (depending on the orientation of the primerrelative to the designated allele) the 3′ nucleotide of theallele-specific primer (i.e., either Primer 1 or Primer 2) that isspecific for that allele.

Description of Table 4

Table 4 provides a list of LD SNPs that are related to and derived fromcertain interrogated SNPs. The interrogated SNPs, which are shown incolumn 1 (which indicates the hCV identification numbers of eachinterrogated SNP) and column 2 (which indicates the public rsidentification numbers of each interrogated SNP) of Table 4, arestatistically significantly associated with psoriasis, as described andshown herein, particularly in Tables 5-11 and in the Examples sectionbelow. The LD SNPs are provided as an example of SNPs which can alsoserve as markers for disease association based on their being in LD withan interrogated SNP. The criteria and process of selecting such LD SNPs,including the calculation of the r² value and the r² threshold value,are described in Example 3, below.

In Table 4, the column labeled “Interrogated SNP” presents each markeras identified by its unique hCV identification number. The columnlabeled “Interrogated rs” presents the publicly known rs identificationnumber for the corresponding hCV number. The column labeled “LD SNP”presents the hCV numbers of the LD SNPs that are derived from theircorresponding interrogated SNPs. The column labeled “LD SNP rs” presentsthe publicly known rs identification number for the corresponding hCVnumber. The column labeled “Power” presents the level of power where ther² threshold is set. For example, when power is set at 0.51, thethreshold r² value calculated therefrom is the minimum r² that an LD SNPmust have in reference to an interrogated SNP, in order for the LD SNPto be classified as a marker capable of being associated with a diseasephenotype at greater than 51% probability. The column labeled “Thresholdr²” presents the minimum value of r² that an LD SNP must meet inreference to an interrogated SNP in order to qualify as an LD SNP. Thecolumn labeled “r²” presents the actual r² value of the LD SNP inreference to the interrogated SNP to which it is related.

Description of Tables 5-11

Tables 5-11 provide the results of statistical analyses for SNPsdisclosed in Tables 1 and 2 (SNPs can be cross-referenced between allthe tables herein based on their hCV and/or rs identification numbers).The results shown in Tables 5-11 provide support for the association ofthese SNPs with psoriasis.

Tables 5-8 are further described in Example 1 below (identification andanalysis of haplotypes in the IL23R region associated with psoriasis).

Table 5 provides information for haplotypes based on the following 5IL23R region SNPs: rs7530511, rs11465804, rs10889671, rs11209026, andrs1857292. For the psoriasis risk (susceptibility) haplotype rs7530511(C), rs11465804 (T), rs10889671 (G), rs11209026 (G), rs1857292 (A), thenaive odds ratio (OR) was 1.391 (P_(comb)=0.000000648). For thepsoriasis non-risk (protective) haplotype rs7530511 (T), rs11465804 (T),rs10889671 (A), rs11209026 (G), rs1857292 (T), the naive odds ratio (OR)was 0.752 (P_(comb)=0.00356). For the psoriasis non-risk (protective)haplotype rs7530511 (C), rs11465804 (G), rs10889671 (G), rs11209026 (A),rs1857292 (A), the naive odds ratio (OR) was 0.599 (P_(comb)=0.0000399).

Table 6 provides information for haplotypes based on the following 3IL23R region SNPs: rs7530511, rs10889671, and rs11209026. For thepsoriasis risk (susceptibility) haplotype rs7530511 (C), rs10889671 (G),rs112090 (G), the naive odds ratio (OR) was 1.436(P_(comb)=0.000000384). For the psoriasis non-risk (protective)haplotype rs7530511 (T), rs10889671 (A), rs112090 (G), the naive oddsratio (OR) was 0.757 (P_(comb)=0.0012). For the psoriasis non-risk(protective) haplotype rs7530511 (C), rs10889671 (G), rs112090 (A), thenaive odds ratio (OR) was 0.588 (P_(comb)=0.00000974).

Table 7 provides information for haplotypes based on the following 23IL23R region SNPs: rs7530511, rs10489629, rs4655692, rs2201841,rs11465804, rs10489628, rs1343152, rs10789229, rs10889671, rs11209026,rs10889674, rs12085634, rs1343151, rs1008193, rs6693831, rs10889675,rs11465827, rs10889677, rs4655531, rs11209030, rs1857292, rs11209031,and rs11209032.

Table 8 provides information for haplotypes based on the following 12IL23R region SNPs: rs2201841, rs10489628, 10889674, rs12085634,rs1008193, rs10889675, rs11465827, rs10889677, rs4655531, rs11209030,rs11209031, and rs11209032.

Tables 9-11 are further described in Example 2 below (identification andanalysis of haplotypes and individual SNPs in the IL12B regionassociated with psoriasis).

Table 9 provides information for haplotypes based on the following 9IL12B region SNPs: rs2546892, rs1433048, rs6894567, rs17860508,rs7709212, rs953861, rs6869411, rs1833754, and rs6861600.

Table 10 provides information for haplotypes based on the following 9IL12B region SNPs: rs1368437, rs2082412, rs7730390, rs3181225,rs1368439, rs3212227, rs3213120, rs3213119, and rs2853696.

Table 11 provides 105 SNPs in the IL12B region that have been identifiedas being associated with psoriasis risk (p-value <0.05). In Table 11,the column labeled “Genotyped or Imputed” indicates whether the dataprovided for the given SNP was derived from genotyping of psoriasissamples or from imputation. See Example 2 below for further informationregarding Table 11.

Tables 5 and 6 indicate case and control counts, with case and controlfrequencies in parentheses. Tables 9 and 10 indicate case and controlfrequencies, with case and control counts in parentheses. Table 7 onlyindicates case and control counts (not frequencies). Table 8 onlyindicates case and control counts in the upper portion of the table, andonly indicates case and control frequencies in the lower portion of thetable. Table 11 indicates case and control frequencies.

In Tables 9 and 10, each of the nine nucleotides of each haplotyperespectively correspond to each of the nine SNPs listed in the columnlabeled “SNP set”.

In Tables 9 and 10, “S0048”, “S0056A”, and “A0019” indicate independentsample sets (i.e., study populations). Specifically, “S0048”, “S0056A”,and “A0019” correspond to “Sample Set 1”, “Sample Set 2”, and “SampleSet 3”, respectively, which are described below in Example 1.

Throughout Tables 5-11, “P”, “P-value”, or “Hap.P” refers to the p-valuefor the given haplotype (or individual SNP in Table 11).

In Tables 5-6 and 9-10, “Comb P” or P_(comb) refers to p-values acrossindependent studies (sample sets).

In Tables 9 and 10, “Global” refers to p-values for all haplotypescombined together within a study (sample set), and “Global Comb P”refers to the p-value for all haplotypes combined together acrossindependent studies (sample sets).

In Table 10, “Other” refers to other haplotypes not listed.

Throughout Tables 5-11, “OR” refers to the odds ratio (“OR95l” and“OR95u” in Table 11 refer to the lower and upper 95% confidenceintervals, respectively, for the odds ratio). Odds ratios (OR) that aregreater than one indicate that a given allele or haplotype is a riskallele/haplotype associated with an increased risk for a given diseasesuch as psoriasis (which may also be referred to as a “susceptibility”allele/haplotype), whereas odds ratios that are less than one indicatethat a given allele or haplotype is a non-risk allele/haplotypeassociated with a decreased risk for a given disease such as psoriasis(which may also be referred to as a “protective” allele/haplotype),particularly as compared to the disease risk for the riskallele/haplotype. For a given risk allele, the other alternative alleleat the SNP position (which can be derived from the information providedin Tables 1-2, for example) may be considered a non-risk allele. For agiven non-risk allele, the other alternative allele at the SNP positionmay be considered a risk allele.

Thus, with respect to disease risk (e.g., psoriasis), if the riskestimate (odds ratio or hazard ratio) for a particular allele at a SNPposition is greater than one, this indicates that an individual withthis particular allele has a higher risk for the disease than anindividual who has the other allele at the SNP position. In contrast, ifthe risk estimate (odds ratio or hazard ratio) for a particular alleleis less than one, this indicates that an individual with this particularallele has a reduced risk for the disease compared with an individualwho has the other allele at the SNP position.

With respect to drug response (e.g., response to an anti-IL12 and/or ananti-IL23 therapy), if the risk estimate (odds ratio or hazard ratio) ofthose treated with the drug (e.g., an anti-IL12 and/or an anti-IL23antibody) compared with those treated with a placebo within a particulargenotype is less than one, this indicates that an individual with thisparticular genotype would benefit from the drug (an odds ratio or hazardratio equal to one would indicate that the drug has no effect). As usedherein, the term “benefit” (with respect to a preventive or therapeuticdrug treatment) is defined as achieving a reduced risk for a diseasethat the drug is intended to treat or prevent (e.g., psoriasis or arelated pathology such as Crohn's disease) by administrating the drugtreatment, compared with the risk for the disease in the absence ofreceiving the drug treatment (or receiving a placebo in lieu of the drugtreatment) for the same genotype.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides SNPs associated with autoinflammatorydiseases such as psoriasis. The present invention further providesnucleic acid molecules containing these SNPs, methods and reagents forthe detection of the SNPs disclosed herein, uses of these SNPs for thedevelopment of detection reagents, and assays or kits that utilize suchreagents. The SNPs disclosed herein are useful for diagnosing,prognosing, screening for, and evaluating predisposition to psoriasisand related pathologies (e.g., Crohn's disease and otherautoinflammatory diseases) in humans, as well as for predicting anindividual's responsiveness to therapies used to treat psoriasis andrelated pathologies. Furthermore, such SNPs and their encoded productsare useful targets for the development of therapeutic and preventiveagents.

A large number of SNPs have been identified from re-sequencing DNA from39 individuals, and they are indicated as “Applera” SNP source in Tables1-2. Their allele frequencies observed in each of the Caucasian andAfrican-American ethnic groups are provided. Additional SNPs includedherein were previously identified during “shotgun” sequencing andassembly of the human genome, and they are indicated as “Celera” SNPsource in Tables 1 and 2. Furthermore, the information provided inTables 1 and 2, particularly the allele frequency information obtainedfrom 39 individuals and the identification of the precise position ofeach SNP within each gene/transcript, allows haplotypes (i.e., groups ofSNPs that are co-inherited) to be readily inferred. The presentinvention encompasses SNP haplotypes, as well as individual SNPs.

Thus, the present invention provides individual SNPs associated withpsoriasis, as well as combinations of SNPs and haplotypes,polymorphic/variant transcript sequences (SEQ ID NOS:1-2) and genomicsequences (SEQ ID NOS:13-20) containing SNPs, encoded amino acidsequences (SEQ ID NOS:3-4), and both transcript-based SNP contextsequences (SEQ ID NOS:5-12) and genomic-based SNP context sequences (SEQID NOS:21-307) (transcript sequences, protein sequences, andtranscript-based SNP context sequences are provided in Table 1 and theSequence Listing; genomic sequences and genomic-based SNP contextsequences are provided in Table 2 and the Sequence Listing), methods ofdetecting these polymorphisms in a test sample, methods of determiningthe risk of an individual of having or developing psoriasis, methods ofdetermining if an individual is likely to respond to a particulartreatment (particularly for treating or preventing psoriasis), methodsof screening for compounds useful for treating disorders associated witha variant gene/protein such as psoriasis, compounds identified by thesescreening methods, methods of using the disclosed SNPs to select atreatment/preventive strategy or therapeutic agent, methods of treatingor preventing a disorder associated with a variant gene/protein, andmethods of using the SNPs of the present invention for humanidentification.

The present invention further provides methods for selecting orformulating a treatment regimen (e.g., methods for determining whetheror not to administer treatment to an individual having psoriasis, or whois at risk for developing psoriasis in the future, or who has previouslyhad psoriasis, methods for selecting a particular treatment regimen suchas dosage and frequency of administration, or a particular form/type ofdrug such as a particular pharmaceutical formulation or compound, etc.),and methods for determining the likelihood of experiencing toxicity orother undesirable side effects from a drug treatment, etc. The presentinvention also provides methods for selecting individuals to whom atherapeutic agent will be administered based on the individual'sgenotype, and methods for selecting individuals for a clinical trial ofa therapeutic agent based on the genotypes of the individuals (e.g.,selecting individuals to participate in the trial who are most likely torespond positively from the drug treatment and/or excluding individualsfrom the trial who are unlikely to respond positively from the drugtreatment based on their SNP genotype(s), or selecting individuals whoare unlikely to respond positively to a particular drug based on theirSNP genotype(s) to participate in a clinical trial of another type ofdrug that may benefit them).

The present invention provides novel SNPs associated with psoriasis, aswell as SNPs that were previously known in the art, but were notpreviously known to be associated with psoriasis. Accordingly, thepresent invention provides novel compositions and methods based on thenovel SNPs disclosed herein, and also provides novel methods of usingthe known, but previously unassociated, SNPs in methods relating toevaluating an individual's likelihood of having or developing psoriasis,predicting the likelihood of an individual experiencing a reccurrence ofpsoriasis, prognosing the severity of psoriasis in an individual, orprognosing an individual's recovery from psoriasis, and methods relatingto evaluating an individual's likelihood of responding to a drugtreatment. In Tables 1 and 2, known SNPs are identified based on thepublic database in which they have been observed, which is indicated asone or more of the following SNP types: “dbSNP”=SNP observed in dbSNP,“HGBASE”=SNP observed in HGBASE, and “HGMD”=SNP observed in the HumanGene Mutation Database (HGMD).

Particular SNP alleles of the present invention can be associated witheither an increased risk of having or developing psoriasis or increasedlikelihood of responding to a drug treatment, or a decreased risk ofhaving or developing psoriasis or decreased likelihood of responding toa drug treatment. Thus, whereas certain SNPs (or their encoded products)can be assayed to determine whether an individual possesses a SNP allelethat is indicative of an increased risk of having or developingpsoriasis or increased likelihood of responding to a drug treatment,other SNPs (or their encoded products) can be assayed to determinewhether an individual possesses a SNP allele that is indicative of adecreased risk of having or developing psoriasis or decreased likelihoodof responding to a drug treatment. Similarly, particular SNP alleles ofthe present invention can be associated with either an increased ordecreased likelihood of having a reccurrence of psoriasis, of fullyrecovering from psoriasis, of experiencing toxic effects from aparticular treatment or therapeutic compound, etc. The term “altered”may be used herein to encompass either of these two possibilities (e.g.,an increased or a decreased risk/likelihood). SNP alleles that areassociated with a decreased risk of having or developing psoriasis maybe referred to as “protective” alleles, and SNP alleles that areassociated with an increased risk of having or developing psoriasis maybe referred to as “susceptibility” alleles, “risk” alleles, or “riskfactors”.

Those skilled in the art will readily recognize that nucleic acidmolecules may be double-stranded molecules and that reference to aparticular site on one strand refers, as well, to the corresponding siteon a complementary strand. In defining a SNP position, SNP allele, ornucleotide sequence, reference to an adenine, a thymine (uridine), acytosine, or a guanine at a particular site on one strand of a nucleicacid molecule also defines the thymine (uridine), adenine, guanine, orcytosine (respectively) at the corresponding site on a complementarystrand of the nucleic acid molecule. Thus, reference may be made toeither strand in order to refer to a particular SNP position, SNPallele, or nucleotide sequence. Probes and primers, may be designed tohybridize to either strand and SNP genotyping methods disclosed hereinmay generally target either strand. Throughout the specification, inidentifying a SNP position, reference is generally made to theprotein-encoding strand, only for the purpose of convenience.

References to variant peptides, polypeptides, or proteins of the presentinvention include peptides, polypeptides, proteins, or fragmentsthereof, that contain at least one amino acid residue that differs fromthe corresponding amino acid sequence of the art-knownpeptide/polypeptide/protein (the art-known protein may beinterchangeably referred to as the “wild-type,” “reference,” or “normal”protein). Such variant peptides/polypeptides/proteins can result from acodon change caused by a nonsynonymous nucleotide substitution at aprotein-coding SNP position (i.e., a missense mutation) disclosed by thepresent invention. Variant peptides/polypeptides/proteins of the presentinvention can also result from a nonsense mutation (i.e., a SNP thatcreates a premature stop codon, a SNP that generates a read-throughmutation by abolishing a stop codon), or due to any SNP disclosed by thepresent invention that otherwise alters the structure, function,activity, or expression of a protein, such as a SNP in a regulatoryregion (e.g. a promoter or enhancer) or a SNP that leads to alternativeor defective splicing, such as a SNP in an intron or a SNP at anexon/intron boundary. As used herein, the terms “polypeptide,”“peptide,” and “protein” are used interchangeably.

As used herein, an “allele” may refer to a nucleotide at a SNP position(wherein at least two alternative nucleotides are present in thepopulation at the SNP position, in accordance with the inherentdefinition of a SNP) or may refer to an amino acid residue that isencoded by the codon which contains the SNP position (where thealternative nucleotides that are present in the population at the SNPposition form alternative codons that encode different amino acidresidues). An “allele” may also be referred to herein as a “variant”.Also, an amino acid residue that is encoded by a codon containing aparticular SNP may simply be referred to as being encoded by the SNP.

A phrase such as “as represented by”, “as shown by”, “as symbolized by”,or “as designated by” may be used herein to refer to a SNP within asequence (e.g., a polynucleotide context sequence surrounding a SNP),such as in the context of “a polymorphism as represented by position 101of SEQ ID NO:X or its complement”. Typically, the sequence surrounding aSNP may be recited when referring to a SNP, however the sequence is notintended as a structural limitation beyond the specific SNP positionitself. Rather, the sequence is recited merely as a way of referring tothe SNP (in this example, “SEQ ID NO:X or its complement” is recited inorder to refer to the SNP located at position 101 of SEQ ID NO:X, butSEQ ID NO:X or its complement is not intended as a structural limitationbeyond the specific SNP position itself). In other words, it isrecognized that the context sequence of SEQ ID NO:X in this example maycontain one or more polymorphic nucleotide positions outside of position101 and therefore an exact match over the full-length of SEQ ID NO:X isirrelevant since SEQ ID NO:X is only meant to provide context forreferring to the SNP at position 101 of SEQ ID NO:X. Likewise, thelength of the context sequence is also irrelevant (100 nucleotides oneach side of a SNP position has been arbitrarily used in the presentapplication as the length for context sequences merely for convenienceand because 201 nucleotides of total length is expected to providesufficient uniqueness to unambiguously identify a given nucleotidesequence). Thus, since a SNP is a variation at a single nucleotideposition, it is customary to refer to context sequence (e.g., SEQ IDNO:X in this example) surrounding a particular SNP position in order touniquely identify and refer to the SNP. Alternatively, a SNP can bereferred to by a unique identification number such as a public “rs”identification number or an internal “hCV” identification number, suchas provided herein for each SNP (e.g., in Tables 1-2).

As used herein, the term “benefit” (with respect to a preventive ortherapeutic drug treatment) is defined as achieving a reduced risk for adisease that the drug is intended to treat or prevent (e.g., psoriasis)by administrating the drug treatment, compared with the risk for thedisease in the absence of receiving the drug treatment (or receiving aplacebo in lieu of the drug treatment) for the same genotype. The term“benefit” may be used herein interchangeably with terms such as “respondpositively” or “positively respond”.

As used herein, the terms “drug” and “therapeutic agent” are usedinterchangeably, and may include, but are not limited to, small moleculecompounds, biologics (e.g., antibodies, proteins, protein fragments,fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g.,antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc.,which may be used for therapeutic and/or preventive treatment of adisease (e.g., psoriasis or Crohn's disease).

As used herein, the term “related pathologies” (e.g., in the context of“psoriasis and related pathologies”) includes inflammatory andautoimmune disorders (collectively referred to herein as“autoinflammatory” diseases/disorders) such as inflammatory boweldisease (IBD) (including Crohn's disease, which further includes bothadult and pediatric Crohn's disease, and ulcerative colitis) and otherchronic inflammatory disorders, atopic dermatitis, multiple sclerosis,rheumatoid arthritis, ankylosing spondylitis (AS), celiac disease,Graves' disease (including Graves' ophthalmopathy (GO) and Graves'disease without opthalmopathy), and Barrett's esophagus.

In addition to autoinflammatory diseases, it is also specificallycontemplated that the SNPs and haplotypes of the invention may also haveutilities with respect to an individual's response to infectiousdiseases (e.g., mycobacterial infections such as tuberculosis andleprosy, as well as Chagas' disease cardiomyopathy and fatal cerebralmalaria), as well as other disorders such as hypertension and stroke.For example, the exemplary SNPs and haplotypes of the invention may beused for determining an individual's susceptibility to these disorders(or the individual's immune response to infectious agents), as well aspsoriasis, Crohn's disease, and related pathologies (such as thepathologies identified in the preceding paragraph). For the role ofIL12B in hypertension and stroke, see Timasheva et al., “Association ofinterleukin-6, interleukin-12, and interleukin-10 gene polymorphismswith essential hypertension in Tatars from Russia”, Biochem Genet. 2008February; 46(1-2):64-74. For the role of IL12B in mycobacterialinfections such as tuberculosis and leprosy, see Morahan et al.,“Association of variants in the IL12B gene with leprosy andtuberculosis”, Tissue Antigens. 2007 April; 69 Suppl 1:234-6. For therole of IL12B in Chagas' disease cardiomyopathy, see Zafra et al.,“Polymorphism in the 3′ UTR of the IL12B gene is associated with Chagas'disease cardiomyopathy”, Microbes Infect. 2007 July; 9(9):1049-52. Forthe role of IL12B in fatal cerebral malaria, see Morahan et al., “Apromoter polymorphism in the gene encoding interleukin-12 p40 (IL12B) isassociated with mortality from cerebral malaria and with reduced nitricoxide production”, Genes Immun. 2002 November; 3(7):414-8.

The following references further describe the roles of IL12B and/orIL23R in psoriasis, Crohn's disease, and other autoinflammatorydiseases, as well as in response to infectious diseases: Schrodi (2008)“Genome-wide association scan in psoriasis: new insights into chronicinflammatory disease”, Expert Rev. Clin. Immunol. 4(5); Duffin et al.,“Genetic variations in cytokines and cytokine receptors associated withpsoriasis found by genome-wide association”, J Invest Dermatol. 2009April; 129(4):827-33; Nair et al (2009) “Genome-wide scan revealsassociation of psoriasis with IL-23 and NF-kappaB pathways”. Nat Genet41(2):199-204; Brown (2009) “Genetics and the pathogenesis of ankylosingspondylitis”. Curr Opin Rheumatol 21(4):318-323; Elder (2009)“Genome-wide association scan yields new insights into theimmunopathogenesis of psoriasis”. Genes Immun 10(3):201-209; Abraham etal. (2009) “Interleukin-23/Th17 pathways and inflammatory boweldisease”. Inflamm Bowel Dis. February 27 [Epub]; Gee et al (2009) “TheIL-12 family of cytokines in infection, inflammation and autoimmunedisorders”. Inflamm Allergy Drug Targets. 8(1):40-52; Kauffman et al.(2004) “A Phase I study evaluating the safety, pharmacokinetics, andclinical response of a human IL-12 p40 antibody in subjects with plaquepsoriasis”. J Inv Dermat 123:1037-1044; Krueger et al. (2007) “A humaninterleukin-12/23 monoclonal antibody for the treatment of psoriasis”. NEngl J Med 356:580-592; Mannon et al. (2004) “Anti-interleukin-12antibody for active Crohn's disease”. N Engl J Med 351: 2069-2079; andPark et al. (2005) “A distinct lineage of CD4 T cells regulates tissueinflammation by producing interleukin 17”. Nat Immun 6:1133-1141.

IL12 and IL23 Therapeutics/Pharmacogenomics in Inflammatory andAutoimmune Disorders

Exemplary embodiments of the invention provide SNPs in the IL12B andIL23R regions that are particularly associated with psoriasis (as shownin the tables and described in the Examples section, for example). TheseSNPs have a variety of therapeutic and pharmacogenomic uses related tothe treatment of psoriasis, as well as other inflammatory and autoimmunedisorders such as inflammatory bowel disease (including Crohn's diseaseand ulcerative colitis), atopic dermatitis, ankylosing spondylitis,rheumatoid arthritis, multiple sclerosis, celiac disease, Graves'disease, and Barrett's esophagus. The psoriasis-associated SNPs providedherein may be used, for example, to determine variability betweendifferent individuals in their response to an inflammatory or autoimmunedisease therapy (e.g., a psoriasis therapy or a therapy for inflammatorybowel disease, Crohn's disease, ulcerative colitis, atopic dermatitis,ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, celiacdisease, Graves' disease, Barrett's esophagus, or other inflammatory orautoimmune disorder) such as to predict whether an individual willrespond positively to a particular therapy, to determine the mosteffective therapeutic agent (e.g., antibody, therapeutic protein, smallmolecule compound, nucleic acid agent, etc.) to use to treat anindividual, to determine whether a particular therapeutic agent shouldor should not be administered to an individual (e.g., by predictingwhether the individual is likely to positively respond to the therapy orby predicting whether the individual will experience toxic or otherundesirable side effects or is unlikely to respond to the therapy), orto determine the therapeutic regimen to use for an individual such asthe dosage or frequency of dosing of a therapeutic agent for aparticular individual. Therapeutic agents that directly modulate (e.g.,inhibit or stimulate) IL12 or IL23 may be used to treat psoriasis,Crohn's disease, or other inflammatory/autoimmune disorders and,furthermore, therapeutic agents that target proteins that interact withIL12 or IL23 or are otherwise in IL12 or IL23 pathways may be used toindirectly modulate IL12 or IL23 to thereby treat psoriasis, Crohn'sdisease, or other inflammatory/autoimmune disorders. Any therapeuticagents such as these may be used in conjunction with the SNPs providedherein.

For example, the IL12 and IL23 psoriasis-associated SNPs provided hereinmay be used to predict whether an individual will respond positively toanti-IL12 and/or anti-IL23 antibody therapy (e.g., anti-IL-12p40antibodies such as ABT-874 (Abbott) and CNTO-1275 (Centocor); seeVeldman, “Targeting the p40 cytokines interleukin (IL)-12 and IL-23 inCrohn's disease”, Drug Discovery Today Therapeutic Strategies, Vol. 3,Issue 3, 2006, pp. 375-380, incorporated herein by reference),especially for Crohn's disease, psoriasis, or other autoinflammatorydiseases, and/or to determine the most effective dosages of thesetherapies. This facilitates decision-making by medical practitioners,such as in deciding whether to administer this therapy to a particularindividual or select another therapy that may be better suited to theindividual, or to use a particular dosage, dosing schedule, or to modifyother aspects of a therapeutic regimen to effectively treat theindividual, for example.

In addition to medical treatment, these uses may also be applied, forexample, in the context of clinical trials of a therapeutic agent (e.g.,a therapeutic agent that targets IL12 or IL23 for the treatment ofpsoriasis, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, atopic dermatitis, ankylosing spondylitis, rheumatoidarthritis, multiple sclerosis, celiac disease, Graves' disease,Barrett's esophagus, or other inflammatory or autoimmune disorders),such as to include particular individuals in a clinical trial who arepredicted to positively respond to the therapeutic agent based on theSNPs provided herein and/or to exclude particular individuals from aclinical trial who are predicted to not positively respond to thetherapeutic agent based on the SNPs provided herein, or to assignindividuals to a particular group within a clinical trial. By using theSNPs provided herein to target a therapeutic agent to individuals whoare more likely to positively respond to the agent, the therapeuticagent is more likely to succeed in clinical trials by showing positiveefficacy and to therefore satisfy the FDA requirements for approval.Additionally, individuals who are more likely to experience toxic orother undesirable side effects may be excluded from being administeredthe therapeutic agent. Furthermore, by using the SNPs provided herein todetermine an effective dosage or dosing frequency, for example, thetherapeutic agent may be less likely to exhibit toxicity or otherundesirable side effects, as well as more likely to achieve positiveefficacy.

Reports, Programmed Computers, Business Methods, and Systems

The results of a test (e.g., an individual's risk for psoriasis, Crohn'sdisease, or other autoinflammatory disease), or an individual'spredicted drug responsiveness (e.g., response to an anti-IL12 oranti-IL23 therapy), based on assaying one or more SNPs disclosed herein,and/or an individual's allele(s)/genotype at one or more SNPs disclosedherein, etc.), and/or any other information pertaining to a test, may bereferred to herein as a “report”. A tangible report can optionally begenerated as part of a testing process (which may be interchangeablyreferred to herein as “reporting”, or as “providing” a report,“producing” a report, or “generating” a report).

Examples of tangible reports may include, but are not limited to,reports in paper (such as computer-generated printouts of test results)or equivalent formats and reports stored on computer readable medium(such as a CD, USB flash drive or other removable storage device,computer hard drive, or computer network server, etc.). Reports,particularly those stored on computer readable medium, can be part of adatabase, which may optionally be accessible via the internet (such as adatabase of patient records or genetic information stored on a computernetwork server, which may be a “secure database” that has securityfeatures that limit access to the report, such as to allow only thepatient and the patient's medical practioners to view the report whilepreventing other unauthorized individuals from viewing the report, forexample). In addition to, or as an alternative to, generating a tangiblereport, reports can also be displayed on a computer screen (or thedisplay of another electronic device or instrument).

A report can include, for example, an individual's risk for psoriasis,Crohn's disease, or other autoinflammatory disease, or may just includethe allele(s)/genotype that an individual carries at one or more SNPsdisclosed herein, which may optionally be linked to informationregarding the significance of having the allele(s)/genotype at the SNP(for example, a report on computer readable medium such as a networkserver may include hyperlink(s) to one or more journal publications orwebsites that describe the medical/biological implications, such asincreased or decreased disease risk, for individuals having a certainallele/genotype at the SNP). Thus, for example, the report can includedisease risk or other medical/biological significance (e.g., drugresponsiveness, etc.) as well as optionally also including theallele/genotype information, or the report may just includeallele/genotype information without including disease risk or othermedical/biological significance (such that an individual viewing thereport can use the allele/genotype information to determine theassociated disease risk or other medical/biological significance from asource outside of the report itself, such as from a medical practioner,publication, website, etc., which may optionally be linked to the reportsuch as by a hyperlink).

A report can further be “transmitted” or “communicated” (these terms maybe used herein interchangeably), such as to the individual who wastested, a medical practitioner (e.g., a doctor, nurse, clinicallaboratory practitioner, genetic counselor, etc.), a healthcareorganization, a clinical laboratory, and/or any other party or requesterintended to view or possess the report. The act of “transmitting” or“communicating” a report can be by any means known in the art, based onthe format of the report. Furthermore, “transmitting” or “communicating”a report can include delivering a report (“pushing”) and/or retrieving(“pulling”) a report. For example, reports can betransmitted/communicated by various means, including being physicallytransferred between parties (such as for reports in paper format) suchas by being physically delivered from one party to another, or by beingtransmitted electronically or in signal form (e.g., via e-mail or overthe internet, by facsimile, and/or by any wired or wirelesscommunication methods known in the art) such as by being retrieved froma database stored on a computer network server, etc.

In certain exemplary embodiments, the invention provides computers (orother apparatus/devices such as biomedical devices or laboratoryinstrumentation) programmed to carry out the methods described herein.For example, in certain embodiments, the invention provides a computerprogrammed to receive (i.e., as input) the identity (e.g., the allele(s)or genotype at a SNP) of one or more SNPs disclosed herein and provide(i.e., as output) the disease risk (e.g., an individual's risk forpsoriasis, Crohn's disease, or other autoinflammatory disease) or otherresult (e.g., disease diagnosis or prognosis, drug responsiveness, etc.)based on the identity of the SNP(s). Such output (e.g., communication ofdisease risk, disease diagnosis or prognosis, drug responsiveness, etc.)may be, for example, in the form of a report on computer readablemedium, printed in paper form, and/or displayed on a computer screen orother display.

In various exemplary embodiments, the invention further provides methodsof doing business (with respect to methods of doing business, the terms“individual” and “customer” are used herein interchangeably). Forexample, exemplary methods of doing business can comprise assaying oneor more SNPs disclosed herein and providing a report that includes, forexample, a customer's risk for psoriasis, Crohn's disease, or otherautoinflammatory disease (based on which allele(s)/genotype is presentat the assayed SNP(s)) and/or that includes the allele(s)/genotype atthe assayed SNP(s) which may optionally be linked to information (e.g.,journal publications, websites, etc.) pertaining to disease risk orother biological/medical significance such as by means of a hyperlink(the report may be provided, for example, on a computer network serveror other computer readable medium that is internet-accessible, and thereport may be included in a secure database that allows the customer toaccess their report while preventing other unauthorized individuals fromviewing the report), and optionally transmitting the report. Customers(or another party who is associated with the customer, such as thecustomer's doctor, for example) can request/order (e.g., purchase) thetest online via the internet (or by phone, mail order, at anoutlet/store, etc.), for example, and a kit can be sent/delivered (orotherwise provided) to the customer (or another party on behalf of thecustomer, such as the customer's doctor, for example) for collection ofa biological sample from the customer (e.g., a buccal swab forcollecting buccal cells), and the customer (or a party who collects thecustomer's biological sample) can submit their biological samples forassaying (e.g., to a laboratory or party associated with the laboratorysuch as a party that accepts the customer samples on behalf of thelaboratory, a party for whom the laboratory is under the control of(e.g., the laboratory carries out the assays by request of the party orunder a contract with the party, for example), and/or a party thatreceives at least a portion of the customer's payment for the test). Thereport (e.g., results of the assay including, for example, thecustomer's disease risk and/or allele(s)/genotype at the assayed SNP(s))may be provided to the customer by, for example, the laboratory thatassays the SNP(s) or a party associated with the laboratory (e.g., aparty that receives at least a portion of the customer's payment for theassay, or a party that requests the laboratory to carry out the assaysor that contracts with the laboratory for the assays to be carried out)or a doctor or other medical practitioner who is associated with (e.g.,employed by or having a consulting or contracting arrangement with) thelaboratory or with a party associated with the laboratory, or the reportmay be provided to a third party (e.g., a doctor, genetic counselor,hospital, etc.) which optionally provides the report to the customer. Infurther embodiments, the customer may be a doctor or other medicalpractitioner, or a hospital, laboratory, medical insurance organization,or other medical organization that requests/orders (e.g., purchases)tests for the purposes of having other individuals (e.g., their patientsor customers) assayed for one or more SNPs disclosed herein andoptionally obtaining a report of the assay results.

In certain exemplary methods of doing business, a kit for collecting abiological sample (e.g., a buccal swab for collecting buccal cells, orother sample collection device) is provided to a medical practitioner(e.g., a physician) which the medical practitioner uses to obtain asample (e.g., buccal cells, saliva, blood, etc.) from a patient, thesample is then sent to a laboratory (e.g., a CLIA-certified laboratory)or other facility that tests the sample for one or more SNPs disclosedherein (e.g., to determine the genotype of one or more SNPs disclosedherein, such as to determine the patient's risk for psoriasis, Crohn'sdisease, or other autoinflammatory disease), and the results of the test(e.g., the patient's genotype at one or more SNPs disclosed hereinand/or the patient's disease risk based on their SNP genotype) areprovided back to the medical practitioner (and/or directly to thepatient and/or to another party such as a hospital, medical insurancecompany, genetic counselor, etc.) who may then provide or otherwiseconvey the results to the patient. The results are typically provided inthe form of a report, such as described above.

In certain further exemplary methods of doing business, kits forcollecting a biological sample from a customer (e.g., a buccal swab forcollecting buccal cells, or other sample collection device) are provided(e.g., for sale), such as at an outlet (e.g., a drug store, pharmacy,general merchandise store, or any other desirable outlet), online viathe internet, by mail order, etc., whereby customers can obtain (e.g.,purchase) the kits, collect their own biological samples, and submit(e.g., send/deliver via mail) their samples to a laboratory (e.g., aCLIA-certified laboratory) or other facility which tests the samples forone or more SNPs disclosed herein (e.g., to determine the genotype ofone or more SNPs disclosed herein, such as to determine the customer'srisk for psoriasis, Crohn's disease, or other autoinflammatory disease)and provides the results of the test (e.g., of the customer's genotypeat one or more SNPs disclosed herein and/or the customer's disease riskbased on their SNP genotype) back to the customer and/or to a thirdparty (e.g., a physician or other medical practitioner, hospital,medical insurance company, genetic counselor, etc.). The results aretypically provided in the form of a report, such as described above. Ifthe results of the test are provided to a third party, then this thirdparty may optionally provide another report to the customer based on theresults of the test (e.g., the result of the test from the laboratorymay provide the customer's genotype at one or more SNPs disclosed hereinwithout disease risk information, and the third party may provide areport of the customer's disease risk based on this genotype result).

Certain further embodiments of the invention provide a system fordetermining an individual's autoinflammatory disease risk (e.g., riskfor psoriasis, Crohn's disease, etc.), or whether an individual willbenefit from anti-IL12 and/or anti-IL23 treatment (or other therapy) inreducing autoinflammatory disease risk. Certain exemplary systemscomprise an integrated “loop” in which an individual (or their medicalpractitioner) requests a determination of such individual'sautoinflammatory disease risk (or drug response, etc.), thisdetermination is carried out by testing a sample from the individual,and then the results of this determination are provided back to therequestor. For example, in certain systems, a sample (e.g., buccalcells, saliva, blood, etc.) is obtained from an individual for testing(the sample may be obtained by the individual or, for example, by amedical practitioner), the sample is submitted to a laboratory (or otherfacility) for testing (e.g., determining the genotype of one or moreSNPs disclosed herein), and then the results of the testing are sent tothe patient (which optionally can be done by first sending the resultsto an intermediary, such as a medical practioner, who then provides orotherwise conveys the results to the individual and/or acts on theresults), thereby forming an integrated loop system for determining anindividual's autoinflammatory disease risk (or drug response, etc.). Theportions of the system in which the results are transmitted (e.g.,between any of a testing facility, a medical practitioner, and/or theindividual) can be carried out by way of electronic or signaltransmission (e.g., by computer such as via e-mail or the internet, byproviding the results on a website or computer network server which mayoptionally be a secure database, by phone or fax, or by any other wiredor wireless transmission methods known in the art). Optionally, thesystem can further include a risk reduction component (i.e., a diseasemanagement system) as part of the integrated loop (for an example of adisease management system, see U.S. Pat. No. 6,770,029, “Diseasemanagement system and method including correlation assessment”). Forexample, the results of the test can be used to reduce the risk of thedisease in the individual who was tested, such as by implementing apreventive therapy regimen (e.g., administration of a drug regimen suchas an anti-IL12 and/or an anti-IL23 therapy for reducingautoinflammatory disease risk), modifying the individual's diet,increasing exercise, reducing stress, and/or implementing any otherphysiological or behavioral modifications in the individual with thegoal of reducing disease risk. For reducing autoinflammatory diseaserisk, this may include any means used in the art for improving aspectsof an individual's health relevant to reducing autoinflammatory diseaserisk. Thus, in exemplary embodiments, the system is controlled by theindividual and/or their medical practioner in that the individual and/ortheir medical practioner requests the test, receives the test resultsback, and (optionally) acts on the test results to reduce theindividual's disease risk, such as by implementing a disease managementsystem.

The various methods described herein, such as correlating the presenceor absence of a polymorphism with an altered (e.g., increased ordecreased) risk (or no altered risk) for psoriasis, Crohn's disease, orother autoinflammatory disease (and/or correlating the presence orabsence of a polymorphism with the predicted response of an individualto a drug such as an anti-IL12 and/or an anti-IL23 therapy), can becarried out by automated methods such as by using a computer (or otherapparatus/devices such as biomedical devices, laboratoryinstrumentation, or other apparatus/devices having a computer processor)programmed to carry out any of the methods described herein. Forexample, computer software (which may be interchangeably referred toherein as a computer program) can perform the step of correlating thepresence or absence of a polymorphism in an individual with an altered(e.g., increased or decreased) risk (or no altered risk) forautoinflammatory disease (particularly risk for psoriasis or Crohn'sdisease) for the individual. Computer software can also perform the stepof correlating the presence or absence of a polymorphism in anindividual with the predicted response of the individual to a drug suchas an anti-IL12 and/or an anti-IL23 therapy. Accordingly, certainembodiments of the invention provide a computer (or otherapparatus/device) programmed to carry out any of the methods describedherein.

Isolated Nucleic Acid Molecules and SNP Detection Reagents & Kits

Tables 1 and 2 provide a variety of information about each SNP of thepresent invention that is associated with psoriasis, including thetranscript sequences (SEQ ID NOS:1-2), genomic sequences (SEQ IDNOS:13-20), and protein sequences (SEQ ID NOS:3-4) of the encoded geneproducts (with the SNPs indicated by IUB codes in the nucleic acidsequences). In addition, Tables 1 and 2 include SNP context sequences,which generally include 100 nucleotide upstream (5′) plus 100nucleotides downstream (3′) of each SNP position (SEQ ID NOS:5-12correspond to transcript-based SNP context sequences disclosed in Table1, and SEQ ID NOS:21-307 correspond to genomic-based context sequencesdisclosed in Table 2), the alternative nucleotides (alleles) at each SNPposition, and additional information about the variant where relevant,such as SNP type (coding, missense, splice site, UTR, etc.), humanpopulations in which the SNP was observed, observed allele frequencies,information about the encoded protein, etc.

Isolated Nucleic Acid Molecules

The present invention provides isolated nucleic acid molecules thatcontain one or more SNPs disclosed Table 1 and/or Table 2. Isolatednucleic acid molecules containing one or more SNPs disclosed in at leastone of Tables 1 and 2 may be interchangeably referred to throughout thepresent text as “SNP-containing nucleic acid molecules.” Isolatednucleic acid molecules may optionally encode a full-length variantprotein or fragment thereof. The isolated nucleic acid molecules of thepresent invention also include probes and primers (which are describedin greater detail below in the section entitled “SNP DetectionReagents”), which may be used for assaying the disclosed SNPs, andisolated full-length genes, transcripts, cDNA molecules, and fragmentsthereof, which may be used for such purposes as expressing an encodedprotein.

As used herein, an “isolated nucleic acid molecule” generally is onethat contains a SNP of the present invention or one that hybridizes tosuch molecule such as a nucleic acid with a complementary sequence, andis separated from most other nucleic acids present in the natural sourceof the nucleic acid molecule. Moreover, an “isolated” nucleic acidmolecule, such as a cDNA molecule containing a SNP of the presentinvention, can be substantially free of other cellular material, orculture medium when produced by recombinant techniques, or chemicalprecursors or other chemicals when chemically synthesized. A nucleicacid molecule can be fused to other coding or regulatory sequences andstill be considered “isolated.” Nucleic acid molecules present innon-human transgenic animals, which do not naturally occur in theanimal, are also considered “isolated.” For example, recombinant DNAmolecules contained in a vector are considered “isolated.” Furtherexamples of “isolated” DNA molecules include recombinant DNA moleculesmaintained in heterologous host cells, and purified (partially orsubstantially) DNA molecules in solution. Isolated RNA molecules includein vivo or in vitro RNA transcripts of the isolated SNP-containing DNAmolecules of the present invention. Isolated nucleic acid moleculesaccording to the present invention further include such moleculesproduced synthetically.

Generally, an isolated SNP-containing nucleic acid molecule comprisesone or more SNP positions disclosed by the present invention withflanking nucleotide sequences on either side of the SNP positions. Aflanking sequence can include nucleotide residues that are naturallyassociated with the SNP site and/or heterologous nucleotide sequences.Preferably, the flanking sequence is up to about 500, 300, 100, 60, 50,30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between)on either side of a SNP position, or as long as the full-length gene orentire protein-coding sequence (or any portion thereof such as an exon),especially if the SNP-containing nucleic acid molecule is to be used toproduce a protein or protein fragment.

For full-length genes and entire protein-coding sequences, a SNPflanking sequence can be, for example, up to about 5 KB, 4 KB, 3 KB, 2KB, 1 KB on either side of the SNP. Furthermore, in such instances theisolated nucleic acid molecule comprises exonic sequences (includingprotein-coding and/or non-coding exonic sequences), but may also includeintronic sequences. Thus, any protein coding sequence may be eithercontiguous or separated by introns. The important point is that thenucleic acid is isolated from remote and unimportant flanking sequencesand is of appropriate length such that it can be subjected to thespecific manipulations or uses described herein such as recombinantprotein expression, preparation of probes and primers for assaying theSNP position, and other uses specific to the SNP-containing nucleic acidsequences.

An isolated SNP-containing nucleic acid molecule can comprise, forexample, a full-length gene or transcript, such as a gene isolated fromgenomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, oran mRNA transcript molecule. Polymorphic transcript sequences arereferred to in Table 1 and provided in the Sequence Listing (SEQ IDNOS:1-2), and polymorphic genomic sequences are referred to in Table 2and provided in the Sequence Listing (SEQ ID NOS:13-20). Furthermore,fragments of such full-length genes and transcripts that contain one ormore SNPs disclosed herein are also encompassed by the presentinvention, and such fragments may be used, for example, to express anypart of a protein, such as a particular functional domain or anantigenic epitope.

Thus, the present invention also encompasses fragments of the nucleicacid sequences as disclosed in Tables 1 and 2 (transcript sequences arereferred to in Table 1 as SEQ ID NOS:1-2, genomic sequences are referredto in Table 2 as SEQ ID NOS:13-20, transcript-based SNP contextsequences are referred to in Table 1 as SEQ ID NOS:5-12, andgenomic-based SNP context sequences are referred to in Table 2 as SEQ IDNOS:21-307) and their complements. The actual sequences referred to inthe tables are provided in the Sequence Listing. A fragment typicallycomprises a contiguous nucleotide sequence at least about 8 or morenucleotides, more preferably at least about 12 or more nucleotides, andeven more preferably at least about 16 or more nucleotides. Furthermore,a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60,80, 100, 150, 200, 250 or 500 nucleotides in length (or any other numberin between). The length of the fragment will be based on its intendeduse. For example, the fragment can encode epitope-bearing regions of avariant peptide or regions of a variant peptide that differ from thenormal/wild-type protein, or can be useful as a polynucleotide probe orprimer. Such fragments can be isolated using the nucleotide sequencesprovided in Table 1 and/or Table 2 for the synthesis of a polynucleotideprobe. A labeled probe can then be used, for example, to screen a cDNAlibrary, genomic DNA library, or mRNA to isolate nucleic acidcorresponding to the coding region. Further, primers can be used inamplification reactions, such as for purposes of assaying one or moreSNPs sites or for cloning specific regions of a gene.

An isolated nucleic acid molecule of the present invention furtherencompasses a SNP-containing polynucleotide that is the product of anyone of a variety of nucleic acid amplification methods, which are usedto increase the copy numbers of a polynucleotide of interest in anucleic acid sample. Such amplification methods are well known in theart, and they include but are not limited to, polymerase chain reaction(PCR) (U.S. Pat. Nos. 4,683,195 and 4,683,202; PCR Technology:Principles and Applications for DNA Amplification, ed. H. A. Erlich,Freeman Press, NY, N.Y. (1992)), ligase chain reaction (LCR) (Wu andWallace, Genomics 4:560 (1989); Landegren et al., Science 241:1077(1988)), strand displacement amplification (SDA) (U.S. Pat. Nos.5,270,184 and 5,422,252), transcription-mediated amplification (TMA)(U.S. Pat. No. 5,399,491), linked linear amplification (LLA) (U.S. Pat.No. 6,027,923) and the like, and isothermal amplification methods suchas nucleic acid sequence based amplification (NASBA) and self-sustainedsequence replication (Guatelli et al., Proc Natl Acad Sci USA 87:1874(1990)). Based on such methodologies, a person skilled in the art canreadily design primers in any suitable regions 5′ and 3′ to a SNPdisclosed herein. Such primers may be used to amplify DNA of any lengthso long that it contains the SNP of interest in its sequence.

As used herein, an “amplified polynucleotide” of the invention is aSNP-containing nucleic acid molecule whose amount has been increased atleast two fold by any nucleic acid amplification method performed invitro as compared to its starting amount in a test sample. In otherpreferred embodiments, an amplified polynucleotide is the result of atleast ten fold, fifty fold, one hundred fold, one thousand fold, or eventen thousand fold increase as compared to its starting amount in a testsample. In a typical PCR amplification, a polynucleotide of interest isoften amplified at least fifty thousand fold in amount over theunamplified genomic DNA, but the precise amount of amplification neededfor an assay depends on the sensitivity of the subsequent detectionmethod used.

Generally, an amplified polynucleotide is at least about 16 nucleotidesin length. More typically, an amplified polynucleotide is at least about20 nucleotides in length. In a preferred embodiment of the invention, anamplified polynucleotide is at least about 30 nucleotides in length. Ina more preferred embodiment of the invention, an amplifiedpolynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides inlength. In yet another preferred embodiment of the invention, anamplified polynucleotide is at least about 100, 200, 300, 400, or 500nucleotides in length. While the total length of an amplifiedpolynucleotide of the invention can be as long as an exon, an intron orthe entire gene where the SNP of interest resides, an amplified productis typically up to about 1,000 nucleotides in length (although certainamplification methods may generate amplified products greater than 1000nucleotides in length). More preferably, an amplified polynucleotide isnot greater than about 600-700 nucleotides in length. It is understoodthat irrespective of the length of an amplified polynucleotide, a SNP ofinterest may be located anywhere along its sequence.

In a specific embodiment of the invention, the amplified product is atleast about 201 nucleotides in length, comprises one of thetranscript-based context sequences or the genomic-based contextsequences shown in Tables 1 and 2. Such a product may have additionalsequences on its 5′ end or 3′ end or both. In another embodiment, theamplified product is about 101 nucleotides in length, and it contains aSNP disclosed herein. Preferably, the SNP is located at the middle ofthe amplified product (e.g., at position 101 in an amplified productthat is 201 nucleotides in length, or at position 51 in an amplifiedproduct that is 101 nucleotides in length), or within 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplifiedproduct. However, as indicated above, the SNP of interest may be locatedanywhere along the length of the amplified product.

The present invention provides isolated nucleic acid molecules thatcomprise, consist of, or consist essentially of one or morepolynucleotide sequences that contain one or more SNPs disclosed herein,complements thereof, and SNP-containing fragments thereof.

Accordingly, the present invention provides nucleic acid molecules thatconsist of any of the nucleotide sequences shown in Table 1 and/or Table2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:1-2,genomic sequences are referred to in Table 2 as SEQ ID NOS:13-20,transcript-based SNP context sequences are referred to in Table 1 as SEQID NOS:5-12, and genomic-based SNP context sequences are referred to inTable 2 as SEQ ID NOS:21-307), or any nucleic acid molecule that encodesany of the variant proteins referred to in Table 1 (SEQ ID NOS:3-4). Theactual sequences referred to in the tables are provided in the SequenceListing. A nucleic acid molecule consists of a nucleotide sequence whenthe nucleotide sequence is the complete nucleotide sequence of thenucleic acid molecule.

The present invention further provides nucleic acid molecules thatconsist essentially of any of the nucleotide sequences referred to inTable 1 and/or Table 2 (transcript sequences are referred to in Table 1as SEQ ID NOS:1-2, genomic sequences are referred to in Table 2 as SEQID NOS:13-20, transcript-based SNP context sequences are referred to inTable 1 as SEQ ID NOS:5-12, and genomic-based SNP context sequences arereferred to in Table 2 as SEQ ID NOS:21-307), or any nucleic acidmolecule that encodes any of the variant proteins referred to in Table 1(SEQ ID NOS:3-4). The actual sequences referred to in the tables areprovided in the Sequence Listing. A nucleic acid molecule consistsessentially of a nucleotide sequence when such a nucleotide sequence ispresent with only a few additional nucleotide residues in the finalnucleic acid molecule.

The present invention further provides nucleic acid molecules thatcomprise any of the nucleotide sequences shown in Table 1 and/or Table 2or a SNP-containing fragment thereof (transcript sequences are referredto in Table 1 as SEQ ID NOS:1-2, genomic sequences are referred to inTable 2 as SEQ ID NOS:13-20, transcript-based SNP context sequences arereferred to in Table 1 as SEQ ID NOS:5-12, and genomic-based SNP contextsequences are referred to in Table 2 as SEQ ID NOS:21-307), or anynucleic acid molecule that encodes any of the variant proteins providedin Table 1 (SEQ ID NOS:3-4). The actual sequences referred to in thetables are provided in the Sequence Listing. A nucleic acid moleculecomprises a nucleotide sequence when the nucleotide sequence is at leastpart of the final nucleotide sequence of the nucleic acid molecule. Insuch a fashion, the nucleic acid molecule can be only the nucleotidesequence or have additional nucleotide residues, such as residues thatare naturally associated with it or heterologous nucleotide sequences.Such a nucleic acid molecule can have one to a few additionalnucleotides or can comprise many more additional nucleotides. A briefdescription of how various types of these nucleic acid molecules can bereadily made and isolated is provided below, and such techniques arewell known to those of ordinary skill in the art. Sambrook and Russell,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y.(2000).

The isolated nucleic acid molecules can encode mature proteins plusadditional amino or carboxyl-terminal amino acids or both, or aminoacids interior to the mature peptide (when the mature form has more thanone peptide chain, for instance). Such sequences may play a role inprocessing of a protein from precursor to a mature form, facilitateprotein trafficking, prolong or shorten protein half-life, or facilitatemanipulation of a protein for assay or production. As generally is thecase in situ, the additional amino acids may be processed away from themature protein by cellular enzymes.

Thus, the isolated nucleic acid molecules include, but are not limitedto, nucleic acid molecules having a sequence encoding a peptide alone, asequence encoding a mature peptide and additional coding sequences suchas a leader or secretory sequence (e.g., a pre-pro or pro-proteinsequence), a sequence encoding a mature peptide with or withoutadditional coding sequences, plus additional non-coding sequences, forexample introns and non-coding 5′ and 3′ sequences such as transcribedbut untranslated sequences that play a role in, for example,transcription, mRNA processing (including splicing and polyadenylationsignals), ribosome binding, and/or stability of mRNA. In addition, thenucleic acid molecules may be fused to heterologous marker sequencesencoding, for example, a peptide that facilitates purification.

Isolated nucleic acid molecules can be in the form of RNA, such as mRNA,or in the form DNA, including cDNA and genomic DNA, which may beobtained, for example, by molecular cloning or produced by chemicalsynthetic techniques or by a combination thereof. Sambrook and Russell,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y.(2000). Furthermore, isolated nucleic acid molecules, particularly SNPdetection reagents such as probes and primers, can also be partially orcompletely in the form of one or more types of nucleic acid analogs,such as peptide nucleic acid (PNA). U.S. Pat. Nos. 5,539,082; 5,527,675;5,623,049; and 5,714,331. The nucleic acid, especially DNA, can bedouble-stranded or single-stranded. Single-stranded nucleic acid can bethe coding strand (sense strand) or the complementary non-coding strand(anti-sense strand). DNA, RNA, or PNA segments can be assembled, forexample, from fragments of the human genome (in the case of DNA or RNA)or single nucleotides, short oligonucleotide linkers, or from a seriesof oligonucleotides, to provide a synthetic nucleic acid molecule.Nucleic acid molecules can be readily synthesized using the sequencesprovided herein as a reference; oligonucleotide and PNA oligomersynthesis techniques are well known in the art. See, e.g., Corey,“Peptide nucleic acids: expanding the scope of nucleic acidrecognition,” Trends Biotechnol 15(6):224-9 (June 1997), and Hyrup etal., “Peptide nucleic acids (PNA): synthesis, properties and potentialapplications,” Bioorg Med Chem 4(1):5-23) (January 1996). Furthermore,large-scale automated oligonucleotide/PNA synthesis (including synthesison an array or bead surface or other solid support) can readily beaccomplished using commercially available nucleic acid synthesizers,such as the Applied Biosystems (Foster City, Calif.) 3900High-Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid SynthesisSystem, and the sequence information provided herein.

The present invention encompasses nucleic acid analogs that containmodified, synthetic, or non-naturally occurring nucleotides orstructural elements or other alternative/modified nucleic acidchemistries known in the art. Such nucleic acid analogs are useful, forexample, as detection reagents (e.g., primers/probes) for detecting oneor more SNPs identified in Table 1 and/or Table 2. Furthermore,kits/systems (such as beads, arrays, etc.) that include these analogsare also encompassed by the present invention. For example, PNAoligomers that are based on the polymorphic sequences of the presentinvention are specifically contemplated. PNA oligomers are analogs ofDNA in which the phosphate backbone is replaced with a peptide-likebackbone. Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters4:1081-1082 (1994); Petersen et al., Bioorganic & Medicinal ChemistryLetters 6:793-796 (1996); Kumar et al., Organic Letters 3(9):1269-1272(2001); WO 96/04000. PNA hybridizes to complementary RNA or DNA withhigher affinity and specificity than conventional oligonucleotides andoligonucleotide analogs. The properties of PNA enable novel molecularbiology and biochemistry applications unachievable with traditionaloligonucleotides and peptides.

Additional examples of nucleic acid modifications that improve thebinding properties and/or stability of a nucleic acid include the use ofbase analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263)and the minor groove binders (U.S. Pat. No. 5,801,115). Thus, referencesherein to nucleic acid molecules, SNP-containing nucleic acid molecules,SNP detection reagents (e.g., probes and primers),oligonucleotides/polynucleotides include PNA oligomers and other nucleicacid analogs. Other examples of nucleic acid analogs andalternative/modified nucleic acid chemistries known in the art aredescribed in Current Protocols in Nucleic Acid Chemistry, John Wiley &Sons, N.Y. (2002).

The present invention further provides nucleic acid molecules thatencode fragments of the variant polypeptides disclosed herein as well asnucleic acid molecules that encode obvious variants of such variantpolypeptides. Such nucleic acid molecules may be naturally occurring,such as paralogs (different locus) and orthologs (different organism),or may be constructed by recombinant DNA methods or by chemicalsynthesis. Non-naturally occurring variants may be made by mutagenesistechniques, including those applied to nucleic acid molecules, cells, ororganisms. Accordingly, the variants can contain nucleotidesubstitutions, deletions, inversions and insertions (in addition to theSNPs disclosed in Tables 1 and 2). Variation can occur in either or boththe coding and non-coding regions. The variations can produceconservative and/or non-conservative amino acid substitutions.

Further variants of the nucleic acid molecules disclosed in Tables 1 and2, such as naturally occurring allelic variants (as well as orthologsand paralogs) and synthetic variants produced by mutagenesis techniques,can be identified and/or produced using methods well known in the art.Such further variants can comprise a nucleotide sequence that shares atleast 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity with a nucleic acid sequence disclosed in Table 1and/or Table 2 (or a fragment thereof) and that includes a novel SNPallele disclosed in Table 1 and/or Table 2. Further, variants cancomprise a nucleotide sequence that encodes a polypeptide that shares atleast 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity with a polypeptide sequence disclosed in Table 1(or a fragment thereof) and that includes a novel SNP allele disclosedin Table 1 and/or Table 2. Thus, an aspect of the present invention thatis specifically contemplated are isolated nucleic acid molecules thathave a certain degree of sequence variation compared with the sequencesshown in Tables 1-2, but that contain a novel SNP allele disclosedherein. In other words, as long as an isolated nucleic acid moleculecontains a novel SNP allele disclosed herein, other portions of thenucleic acid molecule that flank the novel SNP allele can vary to somedegree from the specific transcript, genomic, and context sequencesreferred to and shown in Tables 1 and 2, and can encode a polypeptidethat varies to some degree from the specific polypeptide sequencesreferred to in Table 1.

To determine the percent identity of two amino acid sequences or twonucleotide sequences of two molecules that share sequence homology, thesequences are aligned for optimal comparison purposes (e.g., gaps can beintroduced in one or both of a first and a second amino acid or nucleicacid sequence for optimal alignment and non-homologous sequences can bedisregarded for comparison purposes). In a preferred embodiment, atleast 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of areference sequence is aligned for comparison purposes. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein, amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “homology”). Thepercent identity between the two sequences is a function of the numberof identical positions shared by the sequences, taking into account thenumber of gaps, and the length of each gap, which need to be introducedfor optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. Computational Molecular Biology, A. M. Lesk, ed., OxfordUniversity Press, N.Y (1988); Biocomputing: Informatics and GenomeProjects, D. W. Smith, ed., Academic Press, N.Y. (1993); ComputerAnalysis of Sequence Data, Part 1, A. M. Griffin and H. G. Griffin,eds., Humana Press, N.J. (1994); Sequence Analysis in Molecular Biology,G. von Heinje, ed., Academic Press, N.Y. (1987); and Sequence AnalysisPrimer, M. Gribskov and J. Devereux, eds., M. Stockton Press, N.Y.(1991). In a preferred embodiment, the percent identity between twoamino acid sequences is determined using the Needleman and Wunschalgorithm (J Mol Biol (48):444-453 (1970)) which has been incorporatedinto the GAP program in the GCG software package, using either a Blossom62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6,or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

In yet another preferred embodiment, the percent identity between twonucleotide sequences is determined using the GAP program in the GCGsoftware package using a NWSgapdna.CMP matrix and a gap weight of 40,50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. J.Devereux et al., Nucleic Acids Res. 12(1):387 (1984). In anotherembodiment, the percent identity between two amino acid or nucleotidesequences is determined using the algorithm of E. Myers and W. Miller(CABIOS 4:11-17 (1989)) which has been incorporated into the ALIGNprogram (version 2.0), using a PAM120 weight residue table, a gap lengthpenalty of 12, and a gap penalty of 4.

The nucleotide and amino acid sequences of the present invention canfurther be used as a “query sequence” to perform a search againstsequence databases; for example, to identify other family members orrelated sequences. Such searches can be performed using the NBLAST andXBLAST programs (version 2.0). Altschul et al., J Mol Biol 215:403-10(1990). BLAST nucleotide searches can be performed with the NBLASTprogram, score=100, wordlength=12 to obtain nucleotide sequenceshomologous to the nucleic acid molecules of the invention. BLAST proteinsearches can be performed with the XBLAST program, score=50,wordlength=3 to obtain amino acid sequences homologous to the proteinsof the invention. To obtain gapped alignments for comparison purposes,Gapped BLAST can be utilized. Altschul et al., Nucleic Acids Res25(17):3389-3402 (1997). When utilizing BLAST and gapped BLAST programs,the default parameters of the respective programs (e.g., XBLAST andNBLAST) can be used. In addition to BLAST, examples of other search andsequence comparison programs used in the art include, but are notlimited to, FASTA (Pearson, Methods Mol Biol 25, 365-389 (1994)) andKERR (Dufresne et al., Nat Biotechnol 20(12):1269-71 (December 2002)).For further information regarding bioinformatics techniques, see CurrentProtocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.

The present invention further provides non-coding fragments of thenucleic acid molecules disclosed in Table 1 and/or Table 2. Preferrednon-coding fragments include, but are not limited to, promotersequences, enhancer sequences, intronic sequences, 5′ untranslatedregions (UTRs), 3′ untranslated regions, gene modulating sequences andgene termination sequences. Such fragments are useful, for example, incontrolling heterologous gene expression and in developing screens toidentify gene-modulating agents.

SNP Detection Reagents

In a specific aspect of the present invention, the SNPs disclosed inTable 1 and/or Table 2, and their associated transcript sequences(referred to in Table 1 as SEQ ID NOS:1-2), genomic sequences (referredto in Table 2 as SEQ ID NOS:13-20), and context sequences(transcript-based context sequences are referred to in Table 1 as SEQ IDNOS:5-12; genomic-based context sequences are provided in Table 2 as SEQID NOS:21-307), can be used for the design of SNP detection reagents.The actual sequences referred to in the tables are provided in theSequence Listing. As used herein, a “SNP detection reagent” is a reagentthat specifically detects a specific target SNP position disclosedherein, and that is preferably specific for a particular nucleotide(allele) of the target SNP position (i.e., the detection reagentpreferably can differentiate between different alternative nucleotidesat a target SNP position, thereby allowing the identity of thenucleotide present at the target SNP position to be determined).Typically, such detection reagent hybridizes to a target SNP-containingnucleic acid molecule by complementary base-pairing in a sequencespecific manner, and discriminates the target variant sequence fromother nucleic acid sequences such as an art-known form in a test sample.An example of a detection reagent is a probe that hybridizes to a targetnucleic acid containing one or more of the SNPs referred to in Table 1and/or Table 2. In a preferred embodiment, such a probe candifferentiate between nucleic acids having a particular nucleotide(allele) at a target SNP position from other nucleic acids that have adifferent nucleotide at the same target SNP position. In addition, adetection reagent may hybridize to a specific region 5′ and/or 3′ to aSNP position, particularly a region corresponding to the contextsequences referred to in Table 1 and/or Table 2 (transcript-basedcontext sequences are referred to in Table 1 as SEQ ID NOS:5-12;genomic-based context sequences are referred to in Table 2 as SEQ IDNOS:21-307). Another example of a detection reagent is a primer thatacts as an initiation point of nucleotide extension along acomplementary strand of a target polynucleotide. The SNP sequenceinformation provided herein is also useful for designing primers, e.g.allele-specific primers, to amplify (e.g., using PCR) any SNP of thepresent invention.

In one preferred embodiment of the invention, a SNP detection reagent isan isolated or synthetic DNA or RNA polynucleotide probe or primer orPNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizesto a segment of a target nucleic acid molecule containing a SNPidentified in Table 1 and/or Table 2. A detection reagent in the form ofa polynucleotide may optionally contain modified base analogs,intercalators or minor groove binders. Multiple detection reagents suchas probes may be, for example, affixed to a solid support (e.g., arraysor beads) or supplied in solution (e.g. probe/primer sets for enzymaticreactions such as PCR, RT-PCR, TaqMan assays, or primer-extensionreactions) to form a SNP detection kit.

A probe or primer typically is a substantially purified oligonucleotideor PNA oligomer. Such oligonucleotide typically comprises a region ofcomplementary nucleotide sequence that hybridizes under stringentconditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50,55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between) ormore consecutive nucleotides in a target nucleic acid molecule.Depending on the particular assay, the consecutive nucleotides caneither include the target SNP position, or be a specific region in closeenough proximity 5′ and/or 3′ to the SNP position to carry out thedesired assay.

Other preferred primer and probe sequences can readily be determinedusing the transcript sequences (SEQ ID NOS:1-2), genomic sequences (SEQID NOS:13-20), and SNP context sequences (transcript-based contextsequences are referred to in Table 1 as SEQ ID NOS:5-12; genomic-basedcontext sequences are referred to in Table 2 as SEQ ID NOS:21-307)disclosed in the Sequence Listing and in Tables 1 and 2. The actualsequences referred to in the tables are provided in the SequenceListing. It will be apparent to one of skill in the art that suchprimers and probes are directly useful as reagents for genotyping theSNPs of the present invention, and can be incorporated into anykit/system format.

In order to produce a probe or primer specific for a targetSNP-containing sequence, the gene/transcript and/or context sequencesurrounding the SNP of interest is typically examined using a computeralgorithm that starts at the 5′ or at the 3′ end of the nucleotidesequence. Typical algorithms will then identify oligomers of definedlength that are unique to the gene/SNP context sequence, have a GCcontent within a range suitable for hybridization, lack predictedsecondary structure that may interfere with hybridization, and/orpossess other desired characteristics or that lack other undesiredcharacteristics.

A primer or probe of the present invention is typically at least about 8nucleotides in length. In one embodiment of the invention, a primer or aprobe is at least about 10 nucleotides in length. In a preferredembodiment, a primer or a probe is at least about 12 nucleotides inlength. In a more preferred embodiment, a primer or probe is at leastabout 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length.While the maximal length of a probe can be as long as the targetsequence to be detected, depending on the type of assay in which it isemployed, it is typically less than about 50, 60, 65, or 70 nucleotidesin length. In the case of a primer, it is typically less than about 30nucleotides in length. In a specific preferred embodiment of theinvention, a primer or a probe is within the length of about 18 andabout 28 nucleotides. However, in other embodiments, such as nucleicacid arrays and other embodiments in which probes are affixed to asubstrate, the probes can be longer, such as on the order of 30-70, 75,80, 90, 100, or more nucleotides in length (see the section belowentitled “SNP Detection Kits and Systems”).

For analyzing SNPs, it may be appropriate to use oligonucleotidesspecific for alternative SNP alleles. Such oligonucleotides that detectsingle nucleotide variations in target sequences may be referred to bysuch terms as “allele-specific oligonucleotides,” “allele-specificprobes,” or “allele-specific primers.” The design and use ofallele-specific probes for analyzing polymorphisms is described in,e.g., Mutation Detection: A Practical Approach, Cotton et al., eds.,Oxford University Press (1998); Saiki et al., Nature 324:163-166 (1986);Dattagupta, EP235,726; and Saiki, WO 89/11548.

While the design of each allele-specific primer or probe depends onvariables such as the precise composition of the nucleotide sequencesflanking a SNP position in a target nucleic acid molecule, and thelength of the primer or probe, another factor in the use of primers andprobes is the stringency of the condition under which the hybridizationbetween the probe or primer and the target sequence is performed. Higherstringency conditions utilize buffers with lower ionic strength and/or ahigher reaction temperature, and tend to require a more perfect matchbetween probe/primer and a target sequence in order to form a stableduplex. If the stringency is too high, however, hybridization may notoccur at all. In contrast, lower stringency conditions utilize bufferswith higher ionic strength and/or a lower reaction temperature, andpermit the formation of stable duplexes with more mismatched basesbetween a probe/primer and a target sequence. By way of example and notlimitation, exemplary conditions for high stringency hybridizationconditions using an allele-specific probe are as follows:prehybridization with a solution containing 5× standard saline phosphateEDTA (SSPE), 0.5% NaDodSO₄ (SDS) at 55° C., and incubating probe withtarget nucleic acid molecules in the same solution at the sametemperature, followed by washing with a solution containing 2×SSPE, and0.1% SDS at 55° C. or room temperature.

Moderate stringency hybridization conditions may be used forallele-specific primer extension reactions with a solution containing,e.g., about 50 mM KCl at about 46° C. Alternatively, the reaction may becarried out at an elevated temperature such as 60° C. In anotherembodiment, a moderately stringent hybridization condition suitable foroligonucleotide ligation assay (OLA) reactions wherein two probes areligated if they are completely complementary to the target sequence mayutilize a solution of about 100 mM KCl at a temperature of 46° C.

In a hybridization-based assay, allele-specific probes can be designedthat hybridize to a segment of target DNA from one individual but do nothybridize to the corresponding segment from another individual due tothe presence of different polymorphic forms (e.g., alternative SNPalleles/nucleotides) in the respective DNA segments from the twoindividuals. Hybridization conditions should be sufficiently stringentthat there is a significant detectable difference in hybridizationintensity between alleles, and preferably an essentially binaryresponse, whereby a probe hybridizes to only one of the alleles orsignificantly more strongly to one allele. While a probe may be designedto hybridize to a target sequence that contains a SNP site such that theSNP site aligns anywhere along the sequence of the probe, the probe ispreferably designed to hybridize to a segment of the target sequencesuch that the SNP site aligns with a central position of the probe(e.g., a position within the probe that is at least three nucleotidesfrom either end of the probe). This design of probe generally achievesgood discrimination in hybridization between different allelic forms.

In another embodiment, a probe or primer may be designed to hybridize toa segment of target DNA such that the SNP aligns with either the 5′ mostend or the 3′ most end of the probe or primer. In a specific preferredembodiment that is particularly suitable for use in a oligonucleotideligation assay (U.S. Pat. No. 4,988,617), the 3′ most nucleotide of theprobe aligns with the SNP position in the target sequence.

Oligonucleotide probes and primers may be prepared by methods well knownin the art. Chemical synthetic methods include, but are not limited to,the phosphotriester method described by Narang et al., Methods inEnzymology 68:90 (1979); the phosphodiester method described by Brown etal., Methods in Enzymology 68:109 (1979); the diethylphosphoamidatemethod described by Beaucage et al., Tetrahedron Letters 22:1859 (1981);and the solid support method described in U.S. Pat. No. 4,458,066.

Allele-specific probes are often used in pairs (or, less commonly, insets of 3 or 4, such as if a SNP position is known to have 3 or 4alleles, respectively, or to assay both strands of a nucleic acidmolecule for a target SNP allele), and such pairs may be identicalexcept for a one nucleotide mismatch that represents the allelicvariants at the SNP position. Commonly, one member of a pair perfectlymatches a reference form of a target sequence that has a more common SNPallele (i.e., the allele that is more frequent in the target population)and the other member of the pair perfectly matches a form of the targetsequence that has a less common SNP allele (i.e., the allele that israrer in the target population). In the case of an array, multiple pairsof probes can be immobilized on the same support for simultaneousanalysis of multiple different polymorphisms.

In one type of PCR-based assay, an allele-specific primer hybridizes toa region on a target nucleic acid molecule that overlaps a SNP positionand only primes amplification of an allelic form to which the primerexhibits perfect complementarity. Gibbs, Nucleic Acid Res 17:2427-2448(1989). Typically, the primer's 3′-most nucleotide is aligned with andcomplementary to the SNP position of the target nucleic acid molecule.This primer is used in conjunction with a second primer that hybridizesat a distal site. Amplification proceeds from the two primers, producinga detectable product that indicates which allelic form is present in thetest sample. A control is usually performed with a second pair ofprimers, one of which shows a single base mismatch at the polymorphicsite and the other of which exhibits perfect complementarity to a distalsite. The single-base mismatch prevents amplification or substantiallyreduces amplification efficiency, so that either no detectable productis formed or it is formed in lower amounts or at a slower pace. Themethod generally works most effectively when the mismatch is at the3′-most position of the oligonucleotide (i.e., the 3′-most position ofthe oligonucleotide aligns with the target SNP position) because thisposition is most destabilizing to elongation from the primer (see, e.g.,WO 93/22456). This PCR-based assay can be utilized as part of the TaqManassay, described below.

In a specific embodiment of the invention, a primer of the inventioncontains a sequence substantially complementary to a segment of a targetSNP-containing nucleic acid molecule except that the primer has amismatched nucleotide in one of the three nucleotide positions at the3′-most end of the primer, such that the mismatched nucleotide does notbase pair with a particular allele at the SNP site. In a preferredembodiment, the mismatched nucleotide in the primer is the second fromthe last nucleotide at the 3′-most position of the primer. In a morepreferred embodiment, the mismatched nucleotide in the primer is thelast nucleotide at the 3′-most position of the primer.

In another embodiment of the invention, a SNP detection reagent of theinvention is labeled with a fluorogenic reporter dye that emits adetectable signal. While the preferred reporter dye is a fluorescentdye, any reporter dye that can be attached to a detection reagent suchas an oligonucleotide probe or primer is suitable for use in theinvention. Such dyes include, but are not limited to, Acridine, AMCA,BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin,Erythrosin, Fluorescein, 6-Fam, Tet, Joe, Hex, Oregon Green, Rhodamine,Rhodol Green, Tamra, Rox, and Texas Red.

In yet another embodiment of the invention, the detection reagent may befurther labeled with a quencher dye such as Tamra, especially when thereagent is used as a self-quenching probe such as a TaqMan (U.S. Pat.Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos.5,118,801 and 5,312,728), or other stemless or linear beacon probe(Livak et al., PCR Method Appl 4:357-362 (1995); Tyagi et al., NatureBiotechnology 14:303-308 (1996); Nazarenko et al., Nucl Acids Res25:2516-2521 (1997); U.S. Pat. Nos. 5,866,336 and 6,117,635.

The detection reagents of the invention may also contain other labels,including but not limited to, biotin for streptavidin binding, haptenfor antibody binding, and oligonucleotide for binding to anothercomplementary oligonucleotide such as pairs of zipcodes.

The present invention also contemplates reagents that do not contain (orthat are complementary to) a SNP nucleotide identified herein but thatare used to assay one or more SNPs disclosed herein. For example,primers that flank, but do not hybridize directly to a target SNPposition provided herein are useful in primer extension reactions inwhich the primers hybridize to a region adjacent to the target SNPposition (i.e., within one or more nucleotides from the target SNPsite). During the primer extension reaction, a primer is typically notable to extend past a target SNP site if a particular nucleotide(allele) is present at that target SNP site, and the primer extensionproduct can be detected in order to determine which SNP allele ispresent at the target SNP site. For example, particular ddNTPs aretypically used in the primer extension reaction to terminate primerextension once a ddNTP is incorporated into the extension product (aprimer extension product which includes a ddNTP at the 3′-most end ofthe primer extension product, and in which the ddNTP is a nucleotide ofa SNP disclosed herein, is a composition that is specificallycontemplated by the present invention). Thus, reagents that bind to anucleic acid molecule in a region adjacent to a SNP site and that areused for assaying the SNP site, even though the bound sequences do notnecessarily include the SNP site itself, are also contemplated by thepresent invention.

SNP Detection Kits and Systems

A person skilled in the art will recognize that, based on the SNP andassociated sequence information disclosed herein, detection reagents canbe developed and used to assay any SNP of the present inventionindividually or in combination, and such detection reagents can bereadily incorporated into one of the established kit or system formatswhich are well known in the art. The terms “kits” and “systems,” as usedherein in the context of SNP detection reagents, are intended to referto such things as combinations of multiple SNP detection reagents, orone or more SNP detection reagents in combination with one or more othertypes of elements or components (e.g., other types of biochemicalreagents, containers, packages such as packaging intended for commercialsale, substrates to which SNP detection reagents are attached,electronic hardware components, etc.). Accordingly, the presentinvention further provides SNP detection kits and systems, including butnot limited to, packaged probe and primer sets (e.g. TaqMan probe/primersets), arrays/microarrays of nucleic acid molecules, and beads thatcontain one or more probes, primers, or other detection reagents fordetecting one or more SNPs of the present invention. The kits/systemscan optionally include various electronic hardware components; forexample, arrays (“DNA chips”) and microfluidic systems (“lab-on-a-chip”systems) provided by various manufacturers typically comprise hardwarecomponents. Other kits/systems (e.g., probe/primer sets) may not includeelectronic hardware components, but may be comprised of, for example,one or more SNP detection reagents (along with, optionally, otherbiochemical reagents) packaged in one or more containers.

In some embodiments, a SNP detection kit typically contains one or moredetection reagents and other components (e.g. a buffer, enzymes such asDNA polymerases or ligases, chain extension nucleotides such asdeoxynucleotide triphosphates, and in the case of Sanger-type DNAsequencing reactions, chain terminating nucleotides, positive controlsequences, negative control sequences, and the like) necessary to carryout an assay or reaction, such as amplification and/or detection of aSNP-containing nucleic acid molecule. A kit may further contain meansfor determining the amount of a target nucleic acid, and means forcomparing the amount with a standard, and can comprise instructions forusing the kit to detect the SNP-containing nucleic acid molecule ofinterest. In one embodiment of the present invention, kits are providedwhich contain the necessary reagents to carry out one or more assays todetect one or more SNPs disclosed herein. In a preferred embodiment ofthe present invention, SNP detection kits/systems are in the form ofnucleic acid arrays, or compartmentalized kits, includingmicrofluidic/lab-on-a-chip systems.

SNP detection kits/systems may contain, for example, one or more probes,or pairs of probes, that hybridize to a nucleic acid molecule at or neareach target SNP position. Multiple pairs of allele-specific probes maybe included in the kit/system to simultaneously assay large numbers ofSNPs, at least one of which is a SNP of the present invention. In somekits/systems, the allele-specific probes are immobilized to a substratesuch as an array or bead. For example, the same substrate can compriseallele-specific probes for detecting at least 1; 10; 100; 1000; 10,000;100,000 (or any other number in-between) or substantially all of theSNPs shown in Table 1 and/or Table 2.

The terms “arrays,” “microarrays,” and “DNA chips” are used hereininterchangeably to refer to an array of distinct polynucleotides affixedto a substrate, such as glass, plastic, paper, nylon or other type ofmembrane, filter, chip, or any other suitable solid support. Thepolynucleotides can be synthesized directly on the substrate, orsynthesized separate from the substrate and then affixed to thesubstrate. In one embodiment, the microarray is prepared and usedaccording to the methods described in Chee et al., U.S. Pat. No.5,837,832 and PCT application WO95/11995; D. J. Lockhart et al., NatBiotech 14:1675-1680 (1996); and M. Schena et al., Proc Natl Acad Sci93:10614-10619 (1996), all of which are incorporated herein in theirentirety by reference. In other embodiments, such arrays are produced bythe methods described by Brown et al., U.S. Pat. No. 5,807,522.

Nucleic acid arrays are reviewed in the following references: Zammatteoet al., “New chips for molecular biology and diagnostics,” BiotechnolAnnu Rev 8:85-101 (2002); Sosnowski et al., “Active microelectronicarray system for DNA hybridization, genotyping and pharmacogenomicapplications,” Psychiatr Genet 12(4):181-92 (December 2002); Heller,“DNA microarray technology: devices, systems, and applications,” AnnuRev Biomed Eng 4:129-53 (2002); Epub Mar. 22, 2002; Kolchinsky et al.,“Analysis of SNPs and other genomic variations using gel-based chips,”Hum Mutat 19(4):343-60 (April 2002); and McGall et al., “High-densitygenechip oligonucleotide probe arrays,” Adv Biochem Eng Biotechnol77:21-42 (2002).

Any number of probes, such as allele-specific probes, may be implementedin an array, and each probe or pair of probes can hybridize to adifferent SNP position. In the case of polynucleotide probes, they canbe synthesized at designated areas (or synthesized separately and thenaffixed to designated areas) on a substrate using a light-directedchemical process. Each DNA chip can contain, for example, thousands tomillions of individual synthetic polynucleotide probes arranged in agrid-like pattern and miniaturized (e.g., to the size of a dime).Preferably, probes are attached to a solid support in an ordered,addressable array.

A microarray can be composed of a large number of unique,single-stranded polynucleotides, usually either synthetic antisensepolynucleotides or fragments of cDNAs, fixed to a solid support. Typicalpolynucleotides are preferably about 6-60 nucleotides in length, morepreferably about 15-30 nucleotides in length, and most preferably about18-25 nucleotides in length. For certain types of microarrays or otherdetection kits/systems, it may be preferable to use oligonucleotidesthat are only about 7-20 nucleotides in length. In other types ofarrays, such as arrays used in conjunction with chemiluminescentdetection technology, preferred probe lengths can be, for example, about15-80 nucleotides in length, preferably about 50-70 nucleotides inlength, more preferably about 55-65 nucleotides in length, and mostpreferably about 60 nucleotides in length. The microarray or detectionkit can contain polynucleotides that cover the known 5′ or 3′ sequenceof a gene/transcript or target SNP site, sequential polynucleotides thatcover the full-length sequence of a gene/transcript; or uniquepolynucleotides selected from particular areas along the length of atarget gene/transcript sequence, particularly areas corresponding to oneor more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides usedin the microarray or detection kit can be specific to a SNP or SNPs ofinterest (e.g., specific to a particular SNP allele at a target SNPsite, or specific to particular SNP alleles at multiple different SNPsites), or specific to a polymorphic gene/transcript orgenes/transcripts of interest.

Hybridization assays based on polynucleotide arrays rely on thedifferences in hybridization stability of the probes to perfectlymatched and mismatched target sequence variants. For SNP genotyping, itis generally preferable that stringency conditions used in hybridizationassays are high enough such that nucleic acid molecules that differ fromone another at as little as a single SNP position can be differentiated(e.g., typical SNP hybridization assays are designed so thathybridization will occur only if one particular nucleotide is present ata SNP position, but will not occur if an alternative nucleotide ispresent at that SNP position). Such high stringency conditions may bepreferable when using, for example, nucleic acid arrays ofallele-specific probes for SNP detection. Such high stringencyconditions are described in the preceding section, and are well known tothose skilled in the art and can be found in, for example, CurrentProtocols in Molecular Biology 6.3.1-6.3.6, John Wiley & Sons, N.Y.(1989).

In other embodiments, the arrays are used in conjunction withchemiluminescent detection technology. The following patents and patentapplications, which are all hereby incorporated by reference, provideadditional information pertaining to chemiluminescent detection. U.S.patent applications that describe chemiluminescent approaches formicroarray detection: Ser. Nos. 10/620,332 and 10/620,333. U.S. patentsthat describe methods and compositions of dioxetane for performingchemiluminescent detection: U.S. Pat. Nos. 6,124,478; 6,107,024;5,994,073; 5,981,768; 5,871,938; 5,843,681; 5,800,999 and 5,773,628. Andthe U.S. published application that discloses methods and compositionsfor microarray controls: US2002/0110828.

In one embodiment of the invention, a nucleic acid array can comprise anarray of probes of about 15-25 nucleotides in length. In furtherembodiments, a nucleic acid array can comprise any number of probes, inwhich at least one probe is capable of detecting one or more SNPsdisclosed in Table 1 and/or Table 2, and/or at least one probe comprisesa fragment of one of the sequences selected from the group consisting ofthose disclosed in Table 1, Table 2, the Sequence Listing, and sequencescomplementary thereto, said fragment comprising at least about 8consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, morepreferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or moreconsecutive nucleotides (or any other number in-between) and containing(or being complementary to) a novel SNP allele disclosed in Table 1and/or Table 2. In some embodiments, the nucleotide complementary to theSNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of theprobe, more preferably at the center of said probe.

A polynucleotide probe can be synthesized on the surface of thesubstrate by using a chemical coupling procedure and an ink jetapplication apparatus, as described in PCT application WO95/251116(Baldeschweiler et al.) which is incorporated herein in its entirety byreference. In another aspect, a “gridded” array analogous to a dot (orslot) blot may be used to arrange and link cDNA fragments oroligonucleotides to the surface of a substrate using a vacuum system,thermal, UV, mechanical or chemical bonding procedures. An array, suchas those described above, may be produced by hand or by using availabledevices (slot blot or dot blot apparatus), materials (any suitable solidsupport), and machines (including robotic instruments), and may contain8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other numberwhich lends itself to the efficient use of commercially availableinstrumentation.

Using such arrays or other kits/systems, the present invention providesmethods of identifying the SNPs disclosed herein in a test sample. Suchmethods typically involve incubating a test sample of nucleic acids withan array comprising one or more probes corresponding to at least one SNPposition of the present invention, and assaying for binding of a nucleicacid from the test sample with one or more of the probes. Conditions forincubating a SNP detection reagent (or a kit/system that employs one ormore such SNP detection reagents) with a test sample vary. Incubationconditions depend on such factors as the format employed in the assay,the detection methods employed, and the type and nature of the detectionreagents used in the assay. One skilled in the art will recognize thatany one of the commonly available hybridization, amplification and arrayassay formats can readily be adapted to detect the SNPs disclosedherein.

A SNP detection kit/system of the present invention may includecomponents that are used to prepare nucleic acids from a test sample forthe subsequent amplification and/or detection of a SNP-containingnucleic acid molecule. Such sample preparation components can be used toproduce nucleic acid extracts (including DNA and/or RNA), proteins ormembrane extracts from any bodily fluids (such as blood, serum, plasma,urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin,hair, cells (especially nucleated cells), biopsies, buccal swabs ortissue specimens. The test samples used in the above-described methodswill vary based on such factors as the assay format, nature of thedetection method, and the specific tissues, cells or extracts used asthe test sample to be assayed. Methods of preparing nucleic acids,proteins, and cell extracts are well known in the art and can be readilyadapted to obtain a sample that is compatible with the system utilized.Automated sample preparation systems for extracting nucleic acids from atest sample are commercially available, and examples are Qiagen'sBioRobot 9600, Applied Biosystems' PRISM™ 6700 sample preparationsystem, and Roche Molecular Systems' COBAS AmpliPrep System.

Another form of kit contemplated by the present invention is acompartmentalized kit. A compartmentalized kit includes any kit in whichreagents are contained in separate containers. Such containers include,for example, small glass containers, plastic containers, strips ofplastic, glass or paper, or arraying material such as silica. Suchcontainers allow one to efficiently transfer reagents from onecompartment to another compartment such that the test samples andreagents are not cross-contaminated, or from one container to anothervessel not included in the kit, and the agents or solutions of eachcontainer can be added in a quantitative fashion from one compartment toanother or to another vessel. Such containers may include, for example,one or more containers which will accept the test sample, one or morecontainers which contain at least one probe or other SNP detectionreagent for detecting one or more SNPs of the present invention, one ormore containers which contain wash reagents (such as phosphate bufferedsaline, Tris-buffers, etc.), and one or more containers which containthe reagents used to reveal the presence of the bound probe or other SNPdetection reagents. The kit can optionally further comprise compartmentsand/or reagents for, for example, nucleic acid amplification or otherenzymatic reactions such as primer extension reactions, hybridization,ligation, electrophoresis (preferably capillary electrophoresis), massspectrometry, and/or laser-induced fluorescent detection. The kit mayalso include instructions for using the kit. Exemplary compartmentalizedkits include microfluidic devices known in the art. See, e.g., Weigl etal., “Lab-on-a-chip for drug development,” Adv Drug Deliv Rev55(3):349-77 (February 2003). In such microfluidic devices, thecontainers may be referred to as, for example, microfluidic“compartments,” “chambers,” or “channels.”

Microfluidic devices, which may also be referred to as “lab-on-a-chip”systems, biomedical micro-electro-mechanical systems (bioMEMs), ormulticomponent integrated systems, are exemplary kits/systems of thepresent invention for analyzing SNPs. Such systems miniaturize andcompartmentalize processes such as probe/target hybridization, nucleicacid amplification, and capillary electrophoresis reactions in a singlefunctional device. Such microfluidic devices typically utilize detectionreagents in at least one aspect of the system, and such detectionreagents may be used to detect one or more SNPs of the presentinvention. One example of a microfluidic system is disclosed in U.S.Pat. No. 5,589,136, which describes the integration of PCR amplificationand capillary electrophoresis in chips. Exemplary microfluidic systemscomprise a pattern of microchannels designed onto a glass, silicon,quartz, or plastic wafer included on a microchip. The movements of thesamples may be controlled by electric, electroosmotic or hydrostaticforces applied across different areas of the microchip to createfunctional microscopic valves and pumps with no moving parts. Varyingthe voltage can be used as a means to control the liquid flow atintersections between the micro-machined channels and to change theliquid flow rate for pumping across different sections of the microchip.See, for example, U.S. Pat. No. 6,153,073, Dubrow et al., and U.S. Pat.No. 6,156,181, Parce et al.

For genotyping SNPs, an exemplary microfluidic system may integrate, forexample, nucleic acid amplification, primer extension, capillaryelectrophoresis, and a detection method such as laser inducedfluorescence detection. In a first step of an exemplary process forusing such an exemplary system, nucleic acid samples are amplified,preferably by PCR. Then, the amplification products are subjected toautomated primer extension reactions using ddNTPs (specific fluorescencefor each ddNTP) and the appropriate oligonucleotide primers to carry outprimer extension reactions which hybridize just upstream of the targetedSNP. Once the extension at the 3′ end is completed, the primers areseparated from the unincorporated fluorescent ddNTPs by capillaryelectrophoresis. The separation medium used in capillary electrophoresiscan be, for example, polyacrylamide, polyethyleneglycol or dextran. Theincorporated ddNTPs in the single nucleotide primer extension productsare identified by laser-induced fluorescence detection. Such anexemplary microchip can be used to process, for example, at least 96 to384 samples, or more, in parallel.

Uses of Nucleic Acid Molecules

The nucleic acid molecules of the present invention have a variety ofuses, especially for the diagnosis, prognosis, treatment, and preventionof psoriasis, and for predicting drug response. For example, the nucleicacid molecules of the invention are useful for predicting anindividual's risk for developing psoriasis, for prognosing theprogression of psoriasis (e.g., the severity or consequences ofpsoriasis) in an individual, in evaluating the likelihood of anindividual who has psoriasis (or who is at increased risk for psoriasis)of responding to treatment (or prevention) of psoriasis with a drugtreatment, and/or predicting the likelihood that the individual willexperience toxicity or other undesirable side effects from the drugtreatment, etc. For example, the nucleic acid molecules are useful ashybridization probes, such as for genotyping SNPs in messenger RNA,transcript, cDNA, genomic DNA, amplified DNA or other nucleic acidmolecules, and for isolating full-length cDNA and genomic clonesencoding the variant peptides disclosed in Table 1 as well as theirorthologs.

A probe can hybridize to any nucleotide sequence along the entire lengthof a nucleic acid molecule referred to in Table 1 and/or Table 2.Preferably, a probe of the present invention hybridizes to a region of atarget sequence that encompasses a SNP position indicated in Table 1and/or Table 2. More preferably, a probe hybridizes to a SNP-containingtarget sequence in a sequence-specific manner such that it distinguishesthe target sequence from other nucleotide sequences which vary from thetarget sequence only by which nucleotide is present at the SNP site.Such a probe is particularly useful for detecting the presence of aSNP-containing nucleic acid in a test sample, or for determining whichnucleotide (allele) is present at a particular SNP site (i.e.,genotyping the SNP site).

A nucleic acid hybridization probe may be used for determining thepresence, level, form, and/or distribution of nucleic acid expression.The nucleic acid whose level is determined can be DNA or RNA.Accordingly, probes specific for the SNPs described herein can be usedto assess the presence, expression and/or gene copy number in a givencell, tissue, or organism. These uses are relevant for diagnosis ofdisorders involving an increase or decrease in gene expression relativeto normal levels. In vitro techniques for detection of mRNA include, forexample, Northern blot hybridizations and in situ hybridizations. Invitro techniques for detecting DNA include Southern blot hybridizationsand in situ hybridizations. Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

Probes can be used as part of a diagnostic test kit for identifyingcells or tissues in which a variant protein is expressed, such as bymeasuring the level of a variant protein-encoding nucleic acid (e.g.,mRNA) in a sample of cells from a subject or determining if apolynucleotide contains a SNP of interest.

Thus, the nucleic acid molecules of the invention can be used ashybridization probes to detect the SNPs disclosed herein, therebydetermining whether an individual with the polymorphism(s) is at riskfor developing psoriasis (or has already developed early stagepsoriasis), or the likelihood that an individual will respond positivelyto a drug treatment (including preventive treatment) of psoriasis.Detection of a SNP associated with a disease phenotype provides adiagnostic tool for an active disease and/or genetic predisposition tothe disease.

Furthermore, the nucleic acid molecules of the invention are thereforeuseful for detecting a gene (gene information is disclosed in Table 2,for example) which contains a SNP disclosed herein and/or products ofsuch genes, such as expressed mRNA transcript molecules (transcriptinformation is disclosed in Table 1, for example), and are thus usefulfor detecting gene expression. The nucleic acid molecules can optionallybe implemented in, for example, an array or kit format for use indetecting gene expression.

The nucleic acid molecules of the invention are also useful as primersto amplify any given region of a nucleic acid molecule, particularly aregion containing a SNP identified in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful forconstructing recombinant vectors (described in greater detail below).Such vectors include expression vectors that express a portion of, orall of, any of the variant peptide sequences referred to in Table 1.Vectors also include insertion vectors, used to integrate into anothernucleic acid molecule sequence, such as into the cellular genome, toalter in situ expression of a gene and/or gene product. For example, anendogenous coding sequence can be replaced via homologous recombinationwith all or part of the coding region containing one or morespecifically introduced SNPs.

The nucleic acid molecules of the invention are also useful forexpressing antigenic portions of the variant proteins, particularlyantigenic portions that contain a variant amino acid sequence (e.g., anamino acid substitution) caused by a SNP disclosed in Table 1 and/orTable 2.

The nucleic acid molecules of the invention are also useful forconstructing vectors containing a gene regulatory region of the nucleicacid molecules of the present invention.

The nucleic acid molecules of the invention are also useful fordesigning ribozymes corresponding to all, or a part, of an mRNA moleculeexpressed from a SNP-containing nucleic acid molecule described herein.

The nucleic acid molecules of the invention are also useful forconstructing host cells expressing a part, or all, of the nucleic acidmolecules and variant peptides.

The nucleic acid molecules of the invention are also useful forconstructing transgenic animals expressing all, or a part, of thenucleic acid molecules and variant peptides. The production ofrecombinant cells and transgenic animals having nucleic acid moleculeswhich contain the SNPs disclosed in Table 1 and/or Table 2 allows, forexample, effective clinical design of treatment compounds and dosageregimens.

The nucleic acid molecules of the invention are also useful in assaysfor drug screening to identify compounds that, for example, modulatenucleic acid expression.

The nucleic acid molecules of the invention are also useful in genetherapy in patients whose cells have aberrant gene expression. Thus,recombinant cells, which include a patient's cells that have beenengineered ex vivo and returned to the patient, can be introduced intoan individual where the recombinant cells produce the desired protein totreat the individual.

SNP Genotyping Methods

The process of determining which nucleotide(s) is/are present at each ofone or more SNP positions (such as a SNP position disclosed in Table 1and/or Table 2), for either or both alleles, may be referred to by suchphrases as SNP genotyping, determining the “identity” of a SNP,determining the “content” of a SNP, or determining whichnucleotide(s)/allele(s) is/are present at a SNP position. Thus, theseterms can refer to detecting a single allele (nucleotide) at a SNPposition or can encompass detecting both alleles (nucleotides) at a SNPposition (such as to determine the homozygous or heterozygous state of aSNP position). Furthermore, these terms may also refer to detecting anamino acid residue encoded by a SNP (such as alternative amino acidresidues that are encoded by different codons created by alternativenucleotides at a SNP position).

The present invention provides methods of SNP genotyping, such as foruse in evaluating an individual's risk for developing psoriasis, forevaluating an individual's prognosis for disease severity and recovery,for predicting the likelihood that an individual who has previously hadpsoriasis will have a recurrence of psoriasis again in the future, forimplementing a preventive or treatment regimen for an individual basedon that individual having an increased susceptibility for developingpsoriasis, in evaluating an individual's likelihood of responding to adrug treatment (particularly for treating or preventing psoriasis), inselecting a treatment or preventive regimen (e.g., in deciding whetheror not to administer a drug treatment to an individual having psoriasis,or who is at increased risk for developing psoriasis in the future), orin formulating or selecting a particular treatment or preventive regimensuch as dosage and/or frequency of administration of a treatment orchoosing which form/type of a drug to be administered, such as aparticular pharmaceutical composition or compound, etc.), determiningthe likelihood of experiencing toxicity or other undesirable sideeffects from a drug treatment, or selecting individuals for a clinicaltrial of a drug (e.g., selecting individuals to participate in the trialwho are most likely to respond positively from the drug treatment and/orexcluding individuals from the trial who are unlikely to respondpositively from the drug treatment based on their SNP genotype(s), orselecting individuals who are unlikely to respond positively to aparticular drug based on their SNP genotype(s) to participate in aclinical trial of another type of drug that may benefit them), etc.

Nucleic acid samples can be genotyped to determine which allele(s)is/are present at any given genetic region (e.g., SNP position) ofinterest by methods well known in the art. The neighboring sequence canbe used to design SNP detection reagents such as oligonucleotide probes,which may optionally be implemented in a kit format. Exemplary SNPgenotyping methods are described in Chen et al., “Single nucleotidepolymorphism genotyping: biochemistry, protocol, cost and throughput,”Pharmacogenomics J 3(2):77-96 (2003); Kwok et al., “Detection of singlenucleotide polymorphisms,” Curr Issues Mol Biol 5(2):43-60 (April 2003);Shi, “Technologies for individual genotyping: detection of geneticpolymorphisms in drug targets and disease genes,” Am J Pharmacogenomics2(3):197-205 (2002); and Kwok, “Methods for genotyping single nucleotidepolymorphisms,” Annu Rev Genomics Hum Genet 2:235-58 (2001). Exemplarytechniques for high-throughput SNP genotyping are described inMarnellos, “High-throughput SNP analysis for genetic associationstudies,” Curr Opin Drug Discov Devel 6(3):317-21 (May 2003). Common SNPgenotyping methods include, but are not limited to, TaqMan assays,molecular beacon assays, nucleic acid arrays, allele-specific primerextension, allele-specific PCR, arrayed primer extension, homogeneousprimer extension assays, primer extension with detection by massspectrometry, pyrosequencing, multiplex primer extension sorted ongenetic arrays, ligation with rolling circle amplification, homogeneousligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reactionsorted on genetic arrays, restriction-fragment length polymorphism,single base extension-tag assays, and the Invader assay. Such methodsmay be used in combination with detection mechanisms such as, forexample, luminescence or chemiluminescence detection, fluorescencedetection, time-resolved fluorescence detection, fluorescence resonanceenergy transfer, fluorescence polarization, mass spectrometry, andelectrical detection.

Various methods for detecting polymorphisms include, but are not limitedto, methods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science230:1242 (1985); Cotton et al., PNAS 85:4397 (1988); and Saleeba et al.,Meth. Enzymol 217:286-295 (1992)), comparison of the electrophoreticmobility of variant and wild type nucleic acid molecules (Orita et al.,PNAS 86:2766 (1989); Cotton et al., Mutat Res 285:125-144 (1993); andHayashi et al., Genet Anal Tech Appl 9:73-79 (1992)), and assaying themovement of polymorphic or wild-type fragments in polyacrylamide gelscontaining a gradient of denaturant using denaturing gradient gelelectrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequencevariations at specific locations can also be assessed by nucleaseprotection assays such as RNase and S1 protection or chemical cleavagemethods.

In a preferred embodiment, SNP genotyping is performed using the TaqManassay, which is also known as the 5′ nuclease assay (U.S. Pat. Nos.5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of aspecific amplified product during PCR. The TaqMan assay utilizes anoligonucleotide probe labeled with a fluorescent reporter dye and aquencher dye. The reporter dye is excited by irradiation at anappropriate wavelength, it transfers energy to the quencher dye in thesame probe via a process called fluorescence resonance energy transfer(FRET). When attached to the probe, the excited reporter dye does notemit a signal. The proximity of the quencher dye to the reporter dye inthe intact probe maintains a reduced fluorescence for the reporter. Thereporter dye and quencher dye may be at the 5′ most and the 3′ mostends, respectively, or vice versa. Alternatively, the reporter dye maybe at the 5′ or 3′ most end while the quencher dye is attached to aninternal nucleotide, or vice versa. In yet another embodiment, both thereporter and the quencher may be attached to internal nucleotides at adistance from each other such that fluorescence of the reporter isreduced.

During PCR, the 5′ nuclease activity of DNA polymerase cleaves theprobe, thereby separating the reporter dye and the quencher dye andresulting in increased fluorescence of the reporter. Accumulation of PCRproduct is detected directly by monitoring the increase in fluorescenceof the reporter dye. The DNA polymerase cleaves the probe between thereporter dye and the quencher dye only if the probe hybridizes to thetarget SNP-containing template which is amplified during PCR, and theprobe is designed to hybridize to the target SNP site only if aparticular SNP allele is present.

Preferred TaqMan primer and probe sequences can readily be determinedusing the SNP and associated nucleic acid sequence information providedherein. A number of computer programs, such as Primer Express (AppliedBiosystems, Foster City, Calif.), can be used to rapidly obtain optimalprimer/probe sets. It will be apparent to one of skill in the art thatsuch primers and probes for detecting the SNPs of the present inventionare useful in, for example, screening for individuals who aresusceptible to developing psoriasis and related pathologies, or inscreening individuals who have psoriasis (or who are susceptible topsoriasis) for their likelihood of responding to a drug treatment. Theseprobes and primers can be readily incorporated into a kit format. Thepresent invention also includes modifications of the Taqman assay wellknown in the art such as the use of Molecular Beacon probes (U.S. Pat.Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat. Nos.5,866,336 and 6,117,635).

Another preferred method for genotyping the SNPs of the presentinvention is the use of two oligonucleotide probes in an OLA (see, e.g.,U.S. Pat. No. 4,988,617). In this method, one probe hybridizes to asegment of a target nucleic acid with its 3′ most end aligned with theSNP site. A second probe hybridizes to an adjacent segment of the targetnucleic acid molecule directly 3′ to the first probe. The two juxtaposedprobes hybridize to the target nucleic acid molecule, and are ligated inthe presence of a linking agent such as a ligase if there is perfectcomplementarity between the 3′ most nucleotide of the first probe withthe SNP site. If there is a mismatch, ligation would not occur. Afterthe reaction, the ligated probes are separated from the target nucleicacid molecule, and detected as indicators of the presence of a SNP.

The following patents, patent applications, and published internationalpatent applications, which are all hereby incorporated by reference,provide additional information pertaining to techniques for carrying outvarious types of OLA. The following U.S. patents describe OLA strategiesfor performing SNP detection: U.S. Pat. Nos. 6,027,889; 6,268,148;5,494,810; 5,830,711 and 6,054,564. WO 97/31256 and WO 00/56927 describeOLA strategies for performing SNP detection using universal arrays,wherein a zipcode sequence can be introduced into one of thehybridization probes, and the resulting product, or amplified product,hybridized to a universal zip code array. U.S. application US01/17329(and Ser. No. 09/584,905) describes OLA (or LDR) followed by PCR,wherein zipcodes are incorporated into OLA probes, and amplified PCRproducts are determined by electrophoretic or universal zipcode arrayreadout. U.S. applications 60/427,818, 60/445,636, and 60/445,494describe SNPlex methods and software for multiplexed SNP detection usingOLA followed by PCR, wherein zipcodes are incorporated into OLA probes,and amplified PCR products are hybridized with a zipchute reagent, andthe identity of the SNP determined from electrophoretic readout of thezipchute. In some embodiments, OLA is carried out prior to PCR (oranother method of nucleic acid amplification). In other embodiments, PCR(or another method of nucleic acid amplification) is carried out priorto OLA.

Another method for SNP genotyping is based on mass spectrometry. Massspectrometry takes advantage of the unique mass of each of the fournucleotides of DNA. SNPs can be unambiguously genotyped by massspectrometry by measuring the differences in the mass of nucleic acidshaving alternative SNP alleles. MALDI-TOF (Matrix Assisted LaserDesorption Ionization-Time of Flight) mass spectrometry technology ispreferred for extremely precise determinations of molecular mass, suchas SNPs. Numerous approaches to SNP analysis have been developed basedon mass spectrometry. Preferred mass spectrometry-based methods of SNPgenotyping include primer extension assays, which can also be utilizedin combination with other approaches, such as traditional gel-basedformats and microarrays.

Typically, the primer extension assay involves designing and annealing aprimer to a template PCR amplicon upstream (5′) from a target SNPposition. A mix of dideoxynucleotide triphosphates (ddNTPs) and/ordeoxynucleotide triphosphates (dNTPs) are added to a reaction mixturecontaining template (e.g., a SNP-containing nucleic acid molecule whichhas typically been amplified, such as by PCR), primer, and DNApolymerase. Extension of the primer terminates at the first position inthe template where a nucleotide complementary to one of the ddNTPs inthe mix occurs. The primer can be either immediately adjacent (i.e., thenucleotide at the 3′ end of the primer hybridizes to the nucleotide nextto the target SNP site) or two or more nucleotides removed from the SNPposition. If the primer is several nucleotides removed from the targetSNP position, the only limitation is that the template sequence betweenthe 3′ end of the primer and the SNP position cannot contain anucleotide of the same type as the one to be detected, or this willcause premature termination of the extension primer. Alternatively, ifall four ddNTPs alone, with no dNTPs, are added to the reaction mixture,the primer will always be extended by only one nucleotide, correspondingto the target SNP position. In this instance, primers are designed tobind one nucleotide upstream from the SNP position (i.e., the nucleotideat the 3′ end of the primer hybridizes to the nucleotide that isimmediately adjacent to the target SNP site on the 5′ side of the targetSNP site). Extension by only one nucleotide is preferable, as itminimizes the overall mass of the extended primer, thereby increasingthe resolution of mass differences between alternative SNP nucleotides.Furthermore, mass-tagged ddNTPs can be employed in the primer extensionreactions in place of unmodified ddNTPs. This increases the massdifference between primers extended with these ddNTPs, thereby providingincreased sensitivity and accuracy, and is particularly useful fortyping heterozygous base positions. Mass-tagging also alleviates theneed for intensive sample-preparation procedures and decreases thenecessary resolving power of the mass spectrometer.

The extended primers can then be purified and analyzed by MALDI-TOF massspectrometry to determine the identity of the nucleotide present at thetarget SNP position. In one method of analysis, the products from theprimer extension reaction are combined with light absorbing crystalsthat form a matrix. The matrix is then hit with an energy source such asa laser to ionize and desorb the nucleic acid molecules into thegas-phase. The ionized molecules are then ejected into a flight tube andaccelerated down the tube towards a detector. The time between theionization event, such as a laser pulse, and collision of the moleculewith the detector is the time of flight of that molecule. The time offlight is precisely correlated with the mass-to-charge ratio (m/z) ofthe ionized molecule. Ions with smaller m/z travel down the tube fasterthan ions with larger m/z and therefore the lighter ions reach thedetector before the heavier ions. The time-of-flight is then convertedinto a corresponding, and highly precise, m/z. In this manner, SNPs canbe identified based on the slight differences in mass, and thecorresponding time of flight differences, inherent in nucleic acidmolecules having different nucleotides at a single base position. Forfurther information regarding the use of primer extension assays inconjunction with MALDI-TOF mass spectrometry for SNP genotyping, see,e.g., Wise et al., “A standard protocol for single nucleotide primerextension in the human genome using matrix-assisted laserdesorption/ionization time-of-flight mass spectrometry,” Rapid CommunMass Spectrom 17(11):1195-202 (2003).

The following references provide further information describing massspectrometry-based methods for SNP genotyping: Bocker, “SNP and mutationdiscovery using base-specific cleavage and MALDI-TOF mass spectrometry,”Bioinformatics 19 Suppl 1:144-153 (July 2003); Storm et al., “MALDI-TOFmass spectrometry-based SNP genotyping,” Methods Mol Biol 212:241-62(2003); Jurinke et al., “The use of Mass ARRAY technology for highthroughput genotyping,” Adv Biochem Eng Biotechnol 77:57-74 (2002); andJurinke et al., “Automated genotyping using the DNA MassArraytechnology,” Methods Mol Biol 187:179-92 (2002).

SNPs can also be scored by direct DNA sequencing. A variety of automatedsequencing procedures can be utilized (e.g. Biotechniques 19:448(1995)), including sequencing by mass spectrometry. See, e.g., PCTInternational Publication No. WO 94/16101; Cohen et al., Adv Chromatogr36:127-162 (1996); and Griffin et al., Appl Biochem Biotechnol38:147-159 (1993). The nucleic acid sequences of the present inventionenable one of ordinary skill in the art to readily design sequencingprimers for such automated sequencing procedures. Commercialinstrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730,and 3730x1 DNA Analyzers (Foster City, Calif.), is commonly used in theart for automated sequencing.

Other methods that can be used to genotype the SNPs of the presentinvention include single-strand conformational polymorphism (SSCP), anddenaturing gradient gel electrophoresis (DGGE). Myers et al., Nature313:495 (1985). SSCP identifies base differences by alteration inelectrophoretic migration of single stranded PCR products, as describedin Orita et al., Proc. Nat. Acad. Single-stranded PCR products can begenerated by heating or otherwise denaturing double stranded PCRproducts. Single-stranded nucleic acids may refold or form secondarystructures that are partially dependent on the base sequence. Thedifferent electrophoretic mobilities of single-stranded amplificationproducts are related to base-sequence differences at SNP positions. DGGEdifferentiates SNP alleles based on the different sequence-dependentstabilities and melting properties inherent in polymorphic DNA and thecorresponding differences in electrophoretic migration patterns in adenaturing gradient gel. PCR Technology: Principles and Applications forDNA Amplification Chapter 7, Erlich, ed., W.H. Freeman and Co, N.Y.(1992).

Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can also be usedto score SNPs based on the development or loss of a ribozyme cleavagesite. Perfectly matched sequences can be distinguished from mismatchedsequences by nuclease cleavage digestion assays or by differences inmelting temperature. If the SNP affects a restriction enzyme cleavagesite, the SNP can be identified by alterations in restriction enzymedigestion patterns, and the corresponding changes in nucleic acidfragment lengths determined by gel electrophoresis.

SNP genotyping can include the steps of, for example, collecting abiological sample from a human subject (e.g., sample of tissues, cells,fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA,mRNA or both) from the cells of the sample, contacting the nucleic acidswith one or more primers which specifically hybridize to a region of theisolated nucleic acid containing a target SNP under conditions such thathybridization and amplification of the target nucleic acid regionoccurs, and determining the nucleotide present at the SNP position ofinterest, or, in some assays, detecting the presence or absence of anamplification product (assays can be designed so that hybridizationand/or amplification will only occur if a particular SNP allele ispresent or absent). In some assays, the size of the amplificationproduct is detected and compared to the length of a control sample; forexample, deletions and insertions can be detected by a change in size ofthe amplified product compared to a normal genotype.

SNP genotyping is useful for numerous practical applications, asdescribed below. Examples of such applications include, but are notlimited to, SNP-disease association analysis, disease predispositionscreening, disease diagnosis, disease prognosis, disease progressionmonitoring, determining therapeutic strategies based on an individual'sgenotype (“pharmacogenomics”), developing therapeutic agents based onSNP genotypes associated with a disease or likelihood of responding to adrug, stratifying patient populations for clinical trials of atherapeutic, preventive, or diagnostic agent, predicting the likelihoodthat an individual will experience toxic side effects from a therapeuticagent, and human identification applications such as forensics.

Analysis of Genetic Associations Between SNPs and Phenotypic Traits

SNP genotyping for disease diagnosis, disease predisposition screening,disease prognosis, determining drug responsiveness (pharmacogenomics),drug toxicity screening, and other uses described herein, typicallyrelies on initially establishing a genetic association between one ormore specific SNPs and the particular phenotypic traits of interest.

Different study designs may be used for genetic association studies.Modern Epidemiology 609-622, Lippincott, Williams & Wilkins (1998).Observational studies are most frequently carried out in which theresponse of the patients is not interfered with. The first type ofobservational study identifies a sample of persons in whom the suspectedcause of the disease is present and another sample of persons in whomthe suspected cause is absent, and then the frequency of development ofdisease in the two samples is compared. These sampled populations arecalled cohorts, and the study is a prospective study. The other type ofobservational study is case-control or a retrospective study. In typicalcase-control studies, samples are collected from individuals with thephenotype of interest (cases) such as certain manifestations of adisease, and from individuals without the phenotype (controls) in apopulation (target population) that conclusions are to be drawn from.Then the possible causes of the disease are investigatedretrospectively. As the time and costs of collecting samples incase-control studies are considerably less than those for prospectivestudies, case-control studies are the more commonly used study design ingenetic association studies, at least during the exploration anddiscovery stage.

In both types of observational studies, there may be potentialconfounding factors that should be taken into consideration. Confoundingfactors are those that are associated with both the real cause(s) of thedisease and the disease itself, and they include demographic informationsuch as age, gender, ethnicity as well as environmental factors. Whenconfounding factors are not matched in cases and controls in a study,and are not controlled properly, spurious association results can arise.If potential confounding factors are identified, they should becontrolled for by analysis methods explained below.

In a genetic association study, the cause of interest to be tested is acertain allele or a SNP or a combination of alleles or a haplotype fromseveral SNPs. Thus, tissue specimens (e.g., whole blood) from thesampled individuals may be collected and genomic DNA genotyped for theSNP(s) of interest. In addition to the phenotypic trait of interest,other information such as demographic (e.g., age, gender, ethnicity,etc.), clinical, and environmental information that may influence theoutcome of the trait can be collected to further characterize and definethe sample set. In many cases, these factors are known to be associatedwith diseases and/or SNP allele frequencies. There are likelygene-environment and/or gene-gene interactions as well. Analysis methodsto address gene-environment and gene-gene interactions (for example, theeffects of the presence of both susceptibility alleles at two differentgenes can be greater than the effects of the individual alleles at twogenes combined) are discussed below.

After all the relevant phenotypic and genotypic information has beenobtained, statistical analyses are carried out to determine if there isany significant correlation between the presence of an allele or agenotype with the phenotypic characteristics of an individual.Preferably, data inspection and cleaning are first performed beforecarrying out statistical tests for genetic association. Epidemiologicaland clinical data of the samples can be summarized by descriptivestatistics with tables and graphs. Data validation is preferablyperformed to check for data completion, inconsistent entries, andoutliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests ifdistributions are not normal) may then be used to check for significantdifferences between cases and controls for discrete and continuousvariables, respectively. To ensure genotyping quality, Hardy-Weinbergdisequilibrium tests can be performed on cases and controls separately.Significant deviation from Hardy-Weinberg equilibrium (HWE) in bothcases and controls for individual markers can be indicative ofgenotyping errors. If HWE is violated in a majority of markers, it isindicative of population substructure that should be furtherinvestigated. Moreover, Hardy-Weinberg disequilibrium in cases only canindicate genetic association of the markers with the disease. B. Weir,Genetic Data Analysis, Sinauer (1990).

To test whether an allele of a single SNP is associated with the case orcontrol status of a phenotypic trait, one skilled in the art can compareallele frequencies in cases and controls. Standard chi-squared tests andFisher exact tests can be carried out on a 2×2 table (2 SNP alleles×2outcomes in the categorical trait of interest). To test whethergenotypes of a SNP are associated, chi-squared tests can be carried outon a 3×2 table (3 genotypes×2 outcomes). Score tests are also carriedout for genotypic association to contrast the three genotypicfrequencies (major homozygotes, heterozygotes and minor homozygotes) incases and controls, and to look for trends using 3 different modes ofinheritance, namely dominant (with contrast coefficients 2, −1, −1),additive or allelic (with contrast coefficients 1, 0, −1) and recessive(with contrast coefficients 1, 1, −2). Odds ratios for minor versusmajor alleles, and odds ratios for heterozygote and homozygote variantsversus the wild type genotypes are calculated with the desiredconfidence limits, usually 95%.

In order to control for confounders and to test for interaction andeffect modifiers, stratified analyses may be performed using stratifiedfactors that are likely to be confounding, including demographicinformation such as age, ethnicity, and gender, or an interactingelement or effect modifier, such as a known major gene (e.g., APOE forAlzheimer's disease or HLA genes for autoimmune diseases), orenvironmental factors such as smoking in lung cancer. Stratifiedassociation tests may be carried out using Cochran-Mantel-Haenszel teststhat take into account the ordinal nature of genotypes with 0, 1, and 2variant alleles. Exact tests by StatXact may also be performed whencomputationally possible. Another way to adjust for confounding effectsand test for interactions is to perform stepwise multiple logisticregression analysis using statistical packages such as SAS or R.Logistic regression is a model-building technique in which the bestfitting and most parsimonious model is built to describe the relationbetween the dichotomous outcome (for instance, getting a certain diseaseor not) and a set of independent variables (for instance, genotypes ofdifferent associated genes, and the associated demographic andenvironmental factors). The most common model is one in which the logittransformation of the odds ratios is expressed as a linear combinationof the variables (main effects) and their cross-product terms(interactions). Hosmer and Lemeshow, Applied Logistic Regression, Wiley(2000). To test whether a certain variable or interaction issignificantly associated with the outcome, coefficients in the model arefirst estimated and then tested for statistical significance of theirdeparture from zero.

In addition to performing association tests one marker at a time,haplotype association analysis may also be performed to study a numberof markers that are closely linked together. Haplotype association testscan have better power than genotypic or allelic association tests whenthe tested markers are not the disease-causing mutations themselves butare in linkage disequilibrium with such mutations. The test will even bemore powerful if the disease is indeed caused by a combination ofalleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs thatare very close to each other). In order to perform haplotype associationeffectively, marker-marker linkage disequilibrium measures, both D′ andr², are typically calculated for the markers within a gene to elucidatethe haplotype structure. Recent studies in linkage disequilibriumindicate that SNPs within a gene are organized in block pattern, and ahigh degree of linkage disequilibrium exists within blocks and verylittle linkage disequilibrium exists between blocks. Daly et al, NatureGenetics 29:232-235 (2001). Haplotype association with the diseasestatus can be performed using such blocks once they have beenelucidated.

Haplotype association tests can be carried out in a similar fashion asthe allelic and genotypic association tests. Each haplotype in a gene isanalogous to an allele in a multi-allelic marker. One skilled in the artcan either compare the haplotype frequencies in cases and controls ortest genetic association with different pairs of haplotypes. It has beenproposed that score tests can be done on haplotypes using the program“haplo.score.” Schaid et al, Am J Hum Genet 70:425-434 (2002). In thatmethod, haplotypes are first inferred by EM algorithm and score testsare carried out with a generalized linear model (GLM) framework thatallows the adjustment of other factors.

An important decision in the performance of genetic association tests isthe determination of the significance level at which significantassociation can be declared when the P value of the tests reaches thatlevel. In an exploratory analysis where positive hits will be followedup in subsequent confirmatory testing, an unadjusted P value <0.2 (asignificance level on the lenient side), for example, may be used forgenerating hypotheses for significant association of a SNP with certainphenotypic characteristics of a disease. It is preferred that a p-value<0.05 (a significance level traditionally used in the art) is achievedin order for a SNP to be considered to have an association with adisease. It is more preferred that a p-value <0.01 (a significance levelon the stringent side) is achieved for an association to be declared.When hits are followed up in confirmatory analyses in more samples ofthe same source or in different samples from different sources,adjustment for multiple testing will be performed as to avoid excessnumber of hits while maintaining the experiment-wide error rates at0.05. While there are different methods to adjust for multiple testingto control for different kinds of error rates, a commonly used butrather conservative method is Bonferroni correction to control theexperiment-wise or family-wise error rate. Westfall et al., Multiplecomparisons and multiple tests, SAS Institute (1999). Permutation teststo control for the false discovery rates, FDR, can be more powerful.Benjamini and Hochberg, Journal of the Royal Statistical Society, SeriesB 57:1289-1300 (1995); Westfall and Young, Resampling-based MultipleTesting, Wiley (1993). Such methods to control for multiplicity would bepreferred when the tests are dependent and controlling for falsediscovery rates is sufficient as opposed to controlling for theexperiment-wise error rates.

In replication studies using samples from different populations afterstatistically significant markers have been identified in theexploratory stage, meta-analyses can then be performed by combiningevidence of different studies. Modern Epidemiology 643-673, Lippincott,Williams & Wilkins (1998). If available, association results known inthe art for the same SNPs can be included in the meta-analyses.

Since both genotyping and disease status classification can involveerrors, sensitivity analyses may be performed to see how odds ratios andp-values would change upon various estimates on genotyping and diseaseclassification error rates.

It has been well known that subpopulation-based sampling bias betweencases and controls can lead to spurious results in case-controlassociation studies when prevalence of the disease is associated withdifferent subpopulation groups. Ewens and Spielman, Am J Hum Genet62:450-458 (1995). Such bias can also lead to a loss of statisticalpower in genetic association studies. To detect populationstratification, Pritchard and Rosenberg suggested typing markers thatare unlinked to the disease and using results of association tests onthose markers to determine whether there is any populationstratification. Pritchard et al., Am J Hum Gen 65:220-228 (1999). Whenstratification is detected, the genomic control (GC) method as proposedby Devlin and Roeder can be used to adjust for the inflation of teststatistics due to population stratification. Devlin et al., Biometrics55:997-1004 (1999). The GC method is robust to changes in populationstructure levels as well as being applicable to DNA pooling designs.Devlin et al., Genet Epidem 21:273-284 (2001).

While Pritchard's method recommended using 15-20 unlinked microsatellitemarkers, it suggested using more than 30 biallelic markers to get enoughpower to detect population stratification. For the GC method, it hasbeen shown that about 60-70 biallelic markers are sufficient to estimatethe inflation factor for the test statistics due to populationstratification. Bacanu et al., Am J Hum Genet 66:1933-1944 (2000).Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicatedin a genome scan. Kehoe et al., Hum Mol Genet 8:237-245 (1999).

Once individual risk factors, genetic or non-genetic, have been foundfor the predisposition to disease, the next step is to set up aclassification/prediction scheme to predict the category (for instance,disease or no-disease) that an individual will be in depending on hisgenotypes of associated SNPs and other non-genetic risk factors.Logistic regression for discrete trait and linear regression forcontinuous trait are standard techniques for such tasks. Draper andSmith, Applied Regression Analysis, Wiley (1998). Moreover, othertechniques can also be used for setting up classification. Suchtechniques include, but are not limited to, MART, CART, neural network,and discriminant analyses that are suitable for use in comparing theperformance of different methods. The Elements of Statistical Learning,Hastie, Tibshirani & Friedman, Springer (2002).

Disease Diagnosis and Predisposition Screening

Information on association/correlation between genotypes anddisease-related phenotypes can be exploited in several ways. Forexample, in the case of a highly statistically significant associationbetween one or more SNPs with predisposition to a disease for whichtreatment is available, detection of such a genotype pattern in anindividual may justify immediate administration of treatment, or atleast the institution of regular monitoring of the individual. Detectionof the susceptibility alleles associated with serious disease in acouple contemplating having children may also be valuable to the couplein their reproductive decisions. In the case of a weaker but stillstatistically significant association between a SNP and a human disease,immediate therapeutic intervention or monitoring may not be justifiedafter detecting the susceptibility allele or SNP. Nevertheless, thesubject can be motivated to begin simple life-style changes (e.g., diet,exercise) that can be accomplished at little or no cost to theindividual but would confer potential benefits in reducing the risk ofdeveloping conditions for which that individual may have an increasedrisk by virtue of having the risk allele(s).

The SNPs of the invention may contribute to the development ofpsoriasis, or to responsiveness of an individual to a drug treatment, indifferent ways. Some polymorphisms occur within a protein codingsequence and contribute to disease phenotype by affecting proteinstructure. Other polymorphisms occur in noncoding regions but may exertphenotypic effects indirectly via influence on, for example,replication, transcription, and/or translation. A single SNP may affectmore than one phenotypic trait. Likewise, a single phenotypic trait maybe affected by multiple SNPs in different genes.

As used herein, the terms “diagnose,” “diagnosis,” and “diagnostics”include, but are not limited to, any of the following: detection ofpsoriasis that an individual may presently have,predisposition/susceptibility/predictive screening (i.e., determiningwhether an individual has an increased or decreased risk of developingpsoriasis in the future), prognosing the future course of psoriasis orrecurrence of psoriasis in an individual, determining a particular typeor subclass of psoriasis in an individual who currently or previouslyhad psoriasis, confirming or reinforcing a previously made diagnosis ofpsoriasis, evaluating an individual's likelihood of respondingpositively to a particular treatment or therapeutic agent (particularlytreatment or prevention of psoriasis), determining or selecting atherapeutic or preventive strategy that an individual is most likely topositively respond to (e.g., selecting a particular therapeutic agent,or combination of therapeutic agents, or determining a dosing regimen,etc.), classifying (or confirming/reinforcing) an individual as aresponder/non-responder (or determining a particular subtype ofresponder/non-responder) with respect to the individual's response to adrug treatment, and predicting whether a patient is likely to experiencetoxic effects from a particular treatment or therapeutic compound. Suchdiagnostic uses can be based on the SNPs individually or in a uniquecombination or SNP haplotypes of the present invention.

Haplotypes are particularly useful in that, for example, fewer SNPs canbe genotyped to determine if a particular genomic region harbors a locusthat influences a particular phenotype, such as in linkagedisequilibrium-based SNP association analysis.

Linkage disequilibrium (LD) refers to the co-inheritance of alleles(e.g., alternative nucleotides) at two or more different SNP sites atfrequencies greater than would be expected from the separate frequenciesof occurrence of each allele in a given population. The expectedfrequency of co-occurrence of two alleles that are inheritedindependently is the frequency of the first allele multiplied by thefrequency of the second allele. Alleles that co-occur at expectedfrequencies are said to be in “linkage equilibrium.” In contrast, LDrefers to any non-random genetic association between allele(s) at two ormore different SNP sites, which is generally due to the physicalproximity of the two loci along a chromosome. LD can occur when two ormore SNPs sites are in close physical proximity to each other on a givenchromosome and therefore alleles at these SNP sites will tend to remainunseparated for multiple generations with the consequence that aparticular nucleotide (allele) at one SNP site will show a non-randomassociation with a particular nucleotide (allele) at a different SNPsite located nearby. Hence, genotyping one of the SNP sites will givealmost the same information as genotyping the other SNP site that is inLD.

Various degrees of LD can be encountered between two or more SNPs withthe result being that some SNPs are more closely associated (i.e., instronger LD) than others. Furthermore, the physical distance over whichLD extends along a chromosome differs between different regions of thegenome, and therefore the degree of physical separation between two ormore SNP sites necessary for LD to occur can differ between differentregions of the genome.

For diagnostic purposes and similar uses, if a particular SNP site isfound to be useful for, for example, predicting an individual'ssusceptibility to psoriasis or an individual's response to a drugtreatment, then the skilled artisan would recognize that other SNP siteswhich are in LD with this SNP site would also be useful for the samepurposes. Thus, polymorphisms (e.g., SNPs and/or haplotypes) that arenot the actual disease-causing (causative) polymorphisms, but are in LDwith such causative polymorphisms, are also useful. In such instances,the genotype of the polymorphism(s) that is/are in LD with the causativepolymorphism is predictive of the genotype of the causative polymorphismand, consequently, predictive of the phenotype (e.g., psoriasis, orresponder/non-responder to a drug treatment) that is influenced by thecausative SNP(s). Therefore, polymorphic markers that are in LD withcausative polymorphisms are useful as diagnostic markers, and areparticularly useful when the actual causative polymorphism(s) is/areunknown.

Examples of polymorphisms that can be in LD with one or more causativepolymorphisms (and/or in LD with one or more polymorphisms that have asignificant statistical association with a condition) and thereforeuseful for diagnosing the same condition that the causative/associatedSNP(s) is used to diagnose, include other SNPs in the same gene,protein-coding, or mRNA transcript-coding region as thecausative/associated SNP, other SNPs in the same exon or same intron asthe causative/associated SNP, other SNPs in the same haplotype block asthe causative/associated SNP, other SNPs in the same intergenic regionas the causative/associated SNP, SNPs that are outside but near a gene(e.g., within 6 kb on either side, 5′ or 3′, of a gene boundary) thatharbors a causative/associated SNP, etc. Such useful LD SNPs can beselected from among the SNPs disclosed in Tables 1 and 2, for example.

Linkage disequilibrium in the human genome is reviewed in Wall et al.,“Haplotype blocks and linkage disequilibrium in the human genome,” NatRev Genet 4(8):587-97 (August 2003); Garner et al., “On selectingmarkers for association studies: patterns of linkage disequilibriumbetween two and three diallelic loci,” Genet Epidemiol 24(1):57-67(January 2003); Ardlie et al., “Patterns of linkage disequilibrium inthe human genome,” Nat Rev Genet 3(4):299-309 (April 2002); erratum inNat Rev Genet 3(7):566 (July 2002); and Remm et al., “High-densitygenotyping and linkage disequilibrium in the human genome usingchromosome 22 as a model,” Curr Opin Chem Biol 6(1):24-30 (February2002); J. B. S. Haldane, “The combination of linkage values, and thecalculation of distances between the loci of linked factors,” J Genet8:299-309 (1919); G. Mendel, Versuche über Pflanzen-Hybriden.Verhandlungen des naturforschenden Vereines in Brünn (Proceedings of theNatural History Society of Brünn) (1866); Genes IV, B. Lewin, ed.,Oxford University Press, N.Y. (1990); D. L. Hartl and A. G. ClarkPrinciples of Population Genetics 2^(nd) ed., Sinauer Associates, Inc.,Mass. (1989); J. H. Gillespie Population Genetics: A Concise Guide.2^(nd) ed., Johns Hopkins University Press (2004); R. C. Lewontin, “Theinteraction of selection and linkage. I. General considerations;heterotic models,” Genetics 49:49-67 (1964); P. G. Hoel, Introduction toMathematical Statistics 2^(nd) ed., John Wiley & Sons, Inc., N. Y.(1954); R. R. Hudson, “Two-locus sampling distributions and theirapplication,” Genetics 159:1805-1817 (2001); A. P. Dempster, N. M.Laird, D. B. Rubin, “Maximum likelihood from incomplete data via the EMalgorithm,” J R Stat Soc 39:1-38 (1977); L. Excoffier, M. Slatkin,“Maximum-likelihood estimation of molecular haplotype frequencies in adiploid population,” Mol Biol Evol 12(5):921-927 (1995); D. A. Tregouet,S. Escolano, L. Tiret, A. Mallet, J. L. Golmard, “A new algorithm forhaplotype-based association analysis: the Stochastic-EM algorithm,” AnnHum Genet 68(Pt 2):165-177 (2004); A. D. Long and C. H. Langley C H,“The power of association studies to detect the contribution ofcandidate genetic loci to variation in complex traits,” Genome Research9:720-731 (1999); A. Agresti, Categorical Data Analysis, John Wiley &Sons, Inc., N.Y. (1990); K. Lange, Mathematical and Statistical Methodsfor Genetic Analysis, Springer-Verlag New York, Inc., N.Y. (1997); TheInternational HapMap Consortium, “The International HapMap Project,”Nature 426:789-796 (2003); The International HapMap Consortium, “Ahaplotype map of the human genome,” Nature 437:1299-1320 (2005); G. A.Thorisson, A. V. Smith, L. Krishnan, L. D. Stein, “The InternationalHapMap Project Web Site,” Genome Research 15:1591-1593 (2005); G.McVean, C. C. A. Spencer, R. Chaix, “Perspectives on human geneticvariation from the HapMap project,” PLoS Genetics 1(4):413-418 (2005);J. N. Hirschhorn, M. J. Daly, “Genome-wide association studies forcommon diseases and complex traits,” Nat Genet 6:95-108 (2005); S. J.Schrodi, “A probabilistic approach to large-scale association scans: asemi-Bayesian method to detect disease-predisposing alleles,” SAGMB4(1):31 (2005); W. Y. S. Wang, B. J. Barratt, D. G. Clayton, J. A. Todd,“Genome-wide association studies: theoretical and practical concerns,”Nat Rev Genet 6:109-118 (2005); J. K. Pritchard, M. Przeworski, “Linkagedisequilibrium in humans: models and data,” Am J Hum Genet 69:1-14(2001).

As discussed above, one aspect of the present invention is the discoverythat SNPs that are in certain LD distance with an interrogated SNP canalso be used as valid markers for determining whether an individual hasan increased or decreased risk of having or developing psoriasis. Asused herein, the term “interrogated SNP” refers to SNPs that have beenfound to be associated with an increased or decreased risk of diseaseusing genotyping results and analysis, or other appropriate experimentalmethod as exemplified in the working examples described in thisapplication. As used herein, the term “LD SNP” refers to a SNP that hasbeen characterized as a SNP associating with an increased or decreasedrisk of diseases due to their being in LD with the “interrogated SNP”under the methods of calculation described in the application. Below,applicants describe the methods of calculation with which one ofordinary skilled in the art may determine if a particular SNP is in LDwith an interrogated SNP. The parameter r² is commonly used in thegenetics art to characterize the extent of linkage disequilibriumbetween markers (Hudson, 2001). As used herein, the term “in LD with”refers to a particular SNP that is measured at above the threshold of aparameter such as r² with an interrogated SNP.

It is now common place to directly observe genetic variants in a sampleof chromosomes obtained from a population. Suppose one has genotype dataat two genetic markers located on the same chromosome, for the markers Aand B. Further suppose that two alleles segregate at each of these twomarkers such that alleles A₁ and A₂ can be found at marker A and allelesB₁ and B₂ at marker B. Also assume that these two markers are on a humanautosome. If one is to examine a specific individual and find that theyare heterozygous at both markers, such that their two-marker genotype isA₁A₂B₁B₂, then there are two possible configurations: the individual inquestion could have the alleles A₁B₁ on one chromosome and A₂B₂ on theremaining chromosome; alternatively, the individual could have allelesA₁B₂ on one chromosome and A₂B₁ on the other. The arrangement of alleleson a chromosome is called a haplotype. In this illustration, theindividual could have haplotypes A₁B₁/A₂B₂ or A₁B₂/A₂B₁ (see Hartl andClark (1989) for a more complete description). The concept of linkageequilibrium relates the frequency of haplotypes to the allelefrequencies.

Assume that a sample of individuals is selected from a largerpopulation. Considering the two markers described above, each having twoalleles, there are four possible haplotypes: A₁B₁, A₁B₂, A₂B₁ and A₂B₂.Denote the frequencies of these four haplotypes with the followingnotation.

P ₁₁=freq(A ₁ B ₁)  (1)

P ₁₂=freq(A ₁ B ₂)  (2)

P ₂₁=freq(A ₂ B ₁)  (3)

P ₂₂=freq(A ₂ B ₂)  (4)

The allele frequencies at the two markers are then the sum of differenthaplotype frequencies, it is straightforward to write down a similar setof equations relating single-marker allele frequencies to two-markerhaplotype frequencies:

p ₁=freq(A ₁)=P ₁₁ +P ₁₂  (5)

p ₂=freq(A ₂)=P ₂₁ +P ₂₂  (6)

q ₁=freq(B ₁)=+P ₁₁ +P ₂₁  (7)

q ₂=freq(B ₂)=P ₁₂ +P ₂₂  (8)

Note that the four haplotype frequencies and the allele frequencies ateach marker must sum to a frequency of 1.

P ₁₁ +P ₁₂ +P ₂₁ +P ₂₂=1  (9)

p ₁ +p ₂=1  (10)

q ₁ +q ₂=1  (11)

If there is no correlation between the alleles at the two markers, onewould expect that the frequency of the haplotypes would be approximatelythe product of the composite alleles. Therefore,

P ₁₁ ≈p ₁ q1  (12)

P ₁₂ ≈p ₁ q2  (13)

P ₂₁ ≈p ₂ q1  (14)

P ₂₂ ≈p ₂ q2  (15)

These approximating equations (12)-(15) represent the concept of linkageequilibrium where there is independent assortment between the twomarkers—the alleles at the two markers occur together at random. Theseare represented as approximations because linkage equilibrium andlinkage disequilibrium are concepts typically thought of as propertiesof a sample of chromosomes; and as such they are susceptible tostochastic fluctuations due to the sampling process. Empirically, manypairs of genetic markers will be in linkage equilibrium, but certainlynot all pairs.

Having established the concept of linkage equilibrium above, applicantscan now describe the concept of linkage disequilibrium (LD), which isthe deviation from linkage equilibrium. Since the frequency of the A₁B₁haplotype is approximately the product of the allele frequencies for A₁and B₁ under the assumption of linkage equilibrium as statedmathematically in (12), a simple measure for the amount of departurefrom linkage equilibrium is the difference in these two quantities, D,

D=P ₁₁ −p ₁ q ₁  (16)

D=0 indicates perfect linkage equilibrium. Substantial departures fromD=0 indicates LD in the sample of chromosomes examined. Many propertiesof D are discussed in Lewontin (1964) including the maximum and minimumvalues that D can take. Mathematically, using basic algebra, it can beshown that D can also be written solely in terms of haplotypes:

D=P ₁₁ P ₂₂ −P ₁₂ P ₂₁  (17)

If one transforms D by squaring it and subsequently dividing by theproduct of the allele frequencies of A₁, A₂, B₁ and B₂, the resultingquantity, called r², is equivalent to the square of the Pearson'scorrelation coefficient commonly used in statistics (e.g. Hoel, 1954).

$\begin{matrix}{r^{2} = \frac{D^{2}}{p_{1}p_{2}q_{1}q_{2}}} & (18)\end{matrix}$

As with D, values of r² close to 0 indicate linkage equilibrium betweenthe two markers examined in the sample set. As values of r² increase,the two markers are said to be in linkage disequilibrium. The range ofvalues that r² can take are from 0 to 1. r²=1 when there is a perfectcorrelation between the alleles at the two markers.

In addition, the quantities discussed above are sample-specific. And assuch, it is necessary to formulate notation specific to the samplesstudied. In the approach discussed here, three types of samples are ofprimary interest: (i) a sample of chromosomes from individuals affectedby a disease-related phenotype (cases), (ii) a sample of chromosomesobtained from individuals not affected by the disease-related phenotype(controls), and (iii) a standard sample set used for the construction ofhaplotypes and calculation pairwise linkage disequilibrium. For theallele frequencies used in the development of the method describedbelow, an additional subscript will be added to denote either the caseor control sample sets.

p _(1,cs)=freq(A ₁ in cases)  (19)

p _(2,cs)=freq(A ₂ in cases)  (20)

q _(1,cs)=freq(B ₁ in cases)  (21)

q _(2,cs)=freq(B ₂ in cases)  (22)

Similarly,

p _(1,ct)=freq(A ₁ in controls)  (23)

p _(2,ct)=freq(A ₂ in controls)  (24)

q _(1,ct)=freq(B ₁ in controls)  (25)

q _(2,ct)=freq(B ₂ in controls)  (26)

As a well-accepted sample set is necessary for robust linkagedisequilibrium calculations, data obtained from the International HapMapproject (The International HapMap Consortium 2003, 2005; Thorisson etal, 2005; McVean et al, 2005) can be used for the calculation ofpairwise r² values. Indeed, the samples genotyped for the InternationalHapMap Project were selected to be representative examples from varioushuman sub-populations with sufficient numbers of chromosomes examined todraw meaningful and robust conclusions from the patterns of geneticvariation observed. The International HapMap project website(hapmap.org) contains a description of the project, methods utilized andsamples examined. It is useful to examine empirical data to get a senseof the patterns present in such data.

Haplotype frequencies were explicit arguments in equation (18) above.However, knowing the 2-marker haplotype frequencies requires that phaseto be determined for doubly heterozygous samples. When phase is unknownin the data examined, various algorithms can be used to infer phase fromthe genotype data. This issue was discussed earlier where the doublyheterozygous individual with a 2-SNP genotype of A₁A₂B₁B₂ could have oneof two different sets of chromosomes: A₁B₁/A₂B₂ or B₂/A₂B₁. One suchalgorithm to estimate haplotype frequencies is theexpectation-maximization (EM) algorithm first formalized by Dempster etal. (1977). This algorithm is often used in genetics to infer haplotypefrequencies from genotype data (e.g. Excoffier and Slatkin (1995);Tregouet et al. (2004)). It should be noted that for the two-SNP caseexplored here, EM algorithms have very little error provided that theallele frequencies and sample sizes are not too small. The impact on r²values is typically negligible.

As correlated genetic markers share information, interrogation of SNPmarkers in LD with a disease-associated SNP marker can also havesufficient power to detect disease association (Long and Langley(1999)). The relationship between the power to directly finddisease-associated alleles and the power to indirectly detectdisease-association was investigated by Pritchard and Przeworski (2001).In a straight-forward derivation, it can be shown that the power todetect disease association indirectly at a marker locus in linkagedisequilibrium with a disease-association locus is approximately thesame as the power to detect disease-association directly at thedisease-association locus if the sample size is increased by a factor of

$\frac{1}{r^{2}}$

(the reciprocal of equation 18) at the marker in comparison with thedisease-association locus.

Therefore, if one calculated the power to detect disease-associationindirectly with an experiment having N samples, then equivalent power todirectly detect disease-association (at the actualdisease-susceptibility locus) would necessitate an experiment usingapproximately r²N samples. This elementary relationship between power,sample size and linkage disequilibrium can be used to derive an r²threshold value useful in determining whether or not genotyping markersin linkage disequilibrium with a SNP marker directly associated withdisease status has enough power to indirectly detectdisease-association.

To commence a derivation of the power to detect disease-associatedmarkers through an indirect process, define the effective chromosomalsample size as

$\begin{matrix}{{n = \frac{4N_{cs}N_{ct}}{N_{cs} + N_{ct}}};} & (27)\end{matrix}$

where N_(cs) and N_(ct) are the numbers of diploid cases and controls,respectively. This is necessary to handle situations where the numbersof cases and controls are not equivalent. For equal case and controlsample sizes, N_(cs)=N_(ct)=N, the value of the effective number ofchromosomes is simply n=2N—as expected. Let power be calculated for asignificance level α (such that traditional P-values below α will bedeemed statistically significant). Define the standard Gaussiandistribution function as Φ(). Mathematically,

$\begin{matrix}{{\Phi (x)} = {\frac{1}{\sqrt{2\pi}}{\int_{- \infty}^{x}{^{- \frac{\theta^{2}}{2}}{\theta}}}}} & (28)\end{matrix}$

Alternatively, the following error function notation (Erf) may also beused,

$\begin{matrix}{{\Phi (x)} = {\frac{1}{2}\left\lbrack {1 + {{Erf}\left( \frac{x}{\sqrt{2}} \right)}} \right\rbrack}} & (29)\end{matrix}$

For example, Φ(1.644854)=0.95. The value of r² may be derived to yield apre-specified minimum amount of power to detect disease associationthough indirect interrogation. Noting that the LD SNP marker could bethe one that is carrying the disease-association allele, therefore thatthis approach constitutes a lower-bound model where all indirect powerresults are expected to be at least as large as those interrogated.

Denote by β the error rate for not detecting truly disease-associatedmarkers. Therefore, 1−β is the classical definition of statisticalpower. Substituting the Pritchard-Pzreworski result into the samplesize, the power to detect disease association at a significance level ofα is given by the approximation

$\begin{matrix}{{{1 - \beta} \cong {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - {\alpha/2}}} \right\rbrack}};} & (30)\end{matrix}$

where Z_(u) is the inverse of the standard normal cumulativedistribution evaluated at u (uε(0,1)). Z_(u)=Φ⁻¹(u), whereΦ(Φ⁻¹(u))=Φ⁻¹(Φ(u))=u. For example, setting α=0.05, and therefore1−α/2=0.975, one obtains Z_(0.975)=1.95996. Next, setting power equal toa threshold of a minimum power of T,

$\begin{matrix}{T = {\Phi\left\lbrack {\frac{{q_{1,{cs}} - q_{1,{ct}}}}{\sqrt{\frac{{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}}{r^{2}n}}} - Z_{1 - {\alpha/2}}} \right\rbrack}} & (31)\end{matrix}$

and solving for r², the following threshold r² is obtained:

$\begin{matrix}{{r_{T}^{2} = {\frac{\left\lbrack {{q_{1,{cs}}\left( {1 - q_{1,{cs}}} \right)} + {q_{1,{ct}}\left( {1 - q_{1,{ct}}} \right)}} \right\rbrack}{{n\left( {q_{1,{cs}} - q_{1,{ct}}} \right)}^{2}}\left\lbrack {{\Phi^{- 1}(T)} + Z_{1 - {\alpha/2}}} \right\rbrack}^{2}}{{Or},}} & (32) \\{r_{T}^{2} = {\frac{\left( {Z_{T} + Z_{1 - {\alpha/2}}} \right)^{2}}{n}\left\lbrack \frac{q_{1,{cs}} - \left( q_{1,{cs}} \right)^{2} + q_{1,{ct}} - \left( q_{1,{ct}} \right)^{2}}{\left( {q_{1,{cs}} - q_{1,{ct}}} \right)^{2}} \right\rbrack}} & (33)\end{matrix}$

Suppose that r² is calculated between an interrogated SNP and a numberof other SNPs with varying levels of LD with the interrogated SNP. Thethreshold value r_(T) ² is the minimum value of linkage disequilibriumbetween the interrogated SNP and the potential LD SNPs such that the LDSNP still retains a power greater or equal to T for detectingdisease-association. For example, suppose that SNP rs200 is genotyped ina case-control disease-association study and it is found to beassociated with a disease phenotype. Further suppose that the minorallele frequency in 1,000 case chromosomes was found to be 16% incontrast with a minor allele frequency of 10% in 1,000 controlchromosomes. Given those measurements one could have predicted, prior tothe experiment, that the power to detect disease association at asignificance level of 0.05 was quite high—approximately 98% using a testof allelic association. Applying equation (32) one can calculate aminimum value of r² to indirectly assess disease association assumingthat the minor allele at SNP rs200 is truly disease-predisposing for athreshold level of power. If one sets the threshold level of power to be80%, then r_(T) ²=0.489 given the same significance level and chromosomenumbers as above. Hence, any SNP with a pairwise r² value with rs200greater than 0.489 is expected to have greater than 80% power to detectthe disease association. Further, this is assuming the conservativemodel where the LD SNP is disease-associated only through linkagedisequilibrium with the interrogated SNP rs200.

Imputation

Genotypes of SNPs can be imputed without actually having to be directlygenotyped (referred to as “imputation”), such as by using knownhaplotype information. Imputation is particularly useful for identifyingdisease associations for specific known but ungenotyped SNPs by imputingmissing genotypes to these ungenotyped SNPs. Haplotype information (suchas from the HapMap project by The International HapMap Consortium) canbe used to infer haplotype phase and/or impute genotypes for known SNPsthat are not directly genotyped in a given individual or sample set(such as for a disease association study). In general, imputation isbased on using a reference dataset in which the genotypes of potentialSNPs that are to be tested for disease association have been determinedin multiple individuals (such as in HapMap), and then applying thisreference dataset to infer haplotype phase and/or impute missinggenotypes in additional individuals or samples for SNPs that have notbeen directly genotyped. The HapMap dataset is particularly useful asthe reference dataset, however other datasets can be used. Haplotypephase can be determined based on LD and, since haplotypes can becorrelated with other SNPs within a genomic region due to LD,ungenotyped SNPs can be tested for disease associations (or othertraits) by testing haplotypes or by imputing genotypes to theungenotyped SNPs. The majority of methods used for haplotype phaseinference can also be used to impute missing genotypes, however methodsfor imputing missing genotypes do not necessarily rely on haplotypephase inference (Browning, Hum Genet (2008) 124:439-450). Certainexemplary methods for haplotype phase inference and imputation ofmissing genotypes utilize the BEAGLE genetic analysis program.

Thus, SNPs for which genotypes are imputed can be tested for associationwith a disease or other trait even though these SNPs are not directlygenotyped. The SNPs for which genotypes are imputed can be, for example,SNPs that have genotype data available in HapMap but that are notdirectly genotyped in a particular individual or sample set (such as ina particularly disease association study).

In addition to using a reference dataset (e.g., HapMap) to imputegenotypes of SNPs that are not directly genotyped in a study, imputationcan also be used to impute genotypes of SNPs that were directlygenotyped in a study but for which the genotypes are missing for somereason such as because they failed to pass quality control, andimputation can also be used to combine genotyping results from multiplestudies in which different sets of SNPs were genotyped. For example,genotyping results from multiple different studies can be combined, andgenotypes can be imputed for SNPs that have been genotyped in some, butnot all, of the studies (Browning, Hum Genet (2008) 124:439-450).

For a review of imputation (as well as the BEAGLE program), seeBrowning, “Missing data imputation and haplotype phase inference forgenome-wide association studies”, Hum Genet (2008) 124:439-450,incorporated herein by reference.

The contribution or association of particular SNPs and/or SNP haplotypeswith disease phenotypes, such as psoriasis, enables the SNPs of thepresent invention to be used to develop superior diagnostic testscapable of identifying individuals who express a detectable trait, suchas psoriasis, as the result of a specific genotype, or individuals whosegenotype places them at an increased or decreased risk of developing adetectable trait at a subsequent time as compared to individuals who donot have that genotype. As described herein, diagnostics may be based ona single SNP or a group of SNPs. Combined detection of a plurality ofSNPs (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other numberin-between, or more, of the SNPs provided in Table 1 and/or Table 2)typically increases the probability of an accurate diagnosis. Forexample, the presence of a single SNP known to correlate with psoriasismight indicate a probability of 20% that an individual has or is at riskof developing psoriasis, whereas detection of five SNPs, each of whichcorrelates with psoriasis, might indicate a probability of 80% that anindividual has or is at risk of developing psoriasis. To furtherincrease the accuracy of diagnosis or predisposition screening, analysisof the SNPs of the present invention can be combined with that of otherpolymorphisms or other risk factors of psoriasis, such as diseasesymptoms, pathological characteristics, family history, diet,environmental factors or lifestyle factors.

It will be understood by practitioners skilled in the treatment ordiagnosis of psoriasis that the present invention generally does notintend to provide an absolute identification of individuals who are atrisk (or less at risk) of developing psoriasis, and/or pathologiesrelated to psoriasis, but rather to indicate a certain increased (ordecreased) degree or likelihood of developing the disease based onstatistically significant association results. However, this informationis extremely valuable as it can be used to, for example, initiatepreventive treatments or to allow an individual carrying one or moresignificant SNPs or SNP haplotypes to foresee warning signs such asminor clinical symptoms, or to have regularly scheduled physical examsto monitor for appearance of a condition in order to identify and begintreatment of the condition at an early stage. Particularly with diseasesthat are extremely debilitating or fatal if not treated on time, theknowledge of a potential predisposition, even if this predisposition isnot absolute, would likely contribute in a very significant manner totreatment efficacy.

The diagnostic techniques of the present invention may employ a varietyof methodologies to determine whether a test subject has a SNP or a SNPpattern associated with an increased or decreased risk of developing adetectable trait or whether the individual suffers from a detectabletrait as a result of a particular polymorphism/mutation, including, forexample, methods which enable the analysis of individual chromosomes forhaplotyping, family studies, single sperm DNA analysis, or somatichybrids. The trait analyzed using the diagnostics of the invention maybe any detectable trait that is commonly observed in pathologies anddisorders related to psoriasis.

Another aspect of the present invention relates to a method ofdetermining whether an individual is at risk (or less at risk) ofdeveloping one or more traits or whether an individual expresses one ormore traits as a consequence of possessing a particular trait-causing ortrait-influencing allele. These methods generally involve obtaining anucleic acid sample from an individual and assaying the nucleic acidsample to determine which nucleotide(s) is/are present at one or moreSNP positions, wherein the assayed nucleotide(s) is/are indicative of anincreased or decreased risk of developing the trait or indicative thatthe individual expresses the trait as a result of possessing aparticular trait-causing or trait-influencing allele.

In another embodiment, the SNP detection reagents of the presentinvention are used to determine whether an individual has one or moreSNP allele(s) affecting the level (e.g., the concentration of mRNA orprotein in a sample, etc.) or pattern (e.g., the kinetics of expression,rate of decomposition, stability profile, Km, Vmax, etc.) of geneexpression (collectively, the “gene response” of a cell or bodilyfluid). Such a determination can be accomplished by screening for mRNAor protein expression (e.g., by using nucleic acid arrays, RT-PCR,TaqMan assays, or mass spectrometry), identifying genes having alteredexpression in an individual, genotyping SNPs disclosed in Table 1 and/orTable 2 that could affect the expression of the genes having alteredexpression (e.g., SNPs that are in and/or around the gene(s) havingaltered expression, SNPs in regulatory/control regions, SNPs in and/oraround other genes that are involved in pathways that could affect theexpression of the gene(s) having altered expression, or all SNPs couldbe genotyped), and correlating SNP genotypes with altered geneexpression. In this manner, specific SNP alleles at particular SNP sitescan be identified that affect gene expression.

Therapeutics, Pharmacogenomics, and Drug Development

Therapeutic Methods and Compositions

In certain aspects of the invention, there are provided methods ofassaying (i.e., testing) one or more SNPs provided by the presentinvention in an individual's nucleic acids, and administering atherapeutic or preventive agent to the individual based on the allele(s)present at the SNP(s) having indicated that the individual can benefitfrom the therapeutic or preventive agent.

In further aspects of the invention, there are provided methods ofassaying one or more SNPs provided by the present invention in anindividual's nucleic acids, and administering a diagnostic agent (e.g.,an imaging agent), or otherwise carrying out further diagnosticprocedures on the individual, based on the allele(s) present at theSNP(s) having indicated that the diagnostic agents or diagnosticsprocedures are justified in the individual.

In yet other aspects of the invention, there is provided apharmaceutical pack comprising a therapeutic agent (e.g., a smallmolecule drug, antibody, peptide, antisense or RNAi nucleic acidmolecule, etc.) and a set of instructions for administration of thetherapeutic agent to an individual who has been tested for one or moreSNPs provided by the present invention.

Pharmacogenomics

The present invention provides methods for assessing thepharmacogenomics of a subject harboring particular SNP alleles orhaplotypes to a particular therapeutic agent or pharmaceutical compound,or to a class of such compounds. Pharmacogenomics deals with the roleswhich clinically significant hereditary variations (e.g., SNPs) play inthe response to drugs due to altered drug disposition and/or abnormalaction in affected persons. See, e.g., Roses, Nature 405, 857-865(2000); Gould Rothberg, Nature Biotechnology 19, 209-211 (2001);Eichelbaum, Clin Exp Pharmacol Physiol 23(10-11):983-985 (1996); andLinder, Clin Chem 43(2):254-266 (1997). The clinical outcomes of thesevariations can result in severe toxicity of therapeutic drugs in certainindividuals or therapeutic failure of drugs in certain individuals as aresult of individual variation in metabolism. Thus, the SNP genotype ofan individual can determine the way a therapeutic compound acts on thebody or the way the body metabolizes the compound. For example, SNPs indrug metabolizing enzymes can affect the activity of these enzymes,which in turn can affect both the intensity and duration of drug action,as well as drug metabolism and clearance.

The discovery of SNPs in drug metabolizing enzymes, drug transporters,proteins for pharmaceutical agents, and other drug targets has explainedwhy some patients do not obtain the expected drug effects, show anexaggerated drug effect, or experience serious toxicity from standarddrug dosages. SNPs can be expressed in the phenotype of the extensivemetabolizer and in the phenotype of the poor metabolizer. Accordingly,SNPs may lead to allelic variants of a protein in which one or more ofthe protein functions in one population are different from those inanother population. SNPs and the encoded variant peptides thus providetargets to ascertain a genetic predisposition that can affect treatmentmodality. For example, in a ligand-based treatment, SNPs may give riseto amino terminal extracellular domains and/or other ligand-bindingregions of a receptor that are more or less active in ligand binding,thereby affecting subsequent protein activation. Accordingly, liganddosage would necessarily be modified to maximize the therapeutic effectwithin a given population containing particular SNP alleles orhaplotypes.

As an alternative to genotyping, specific variant proteins containingvariant amino acid sequences encoded by alternative SNP alleles could beidentified. Thus, pharmacogenomic characterization of an individualpermits the selection of effective compounds and effective dosages ofsuch compounds for prophylactic or therapeutic uses based on theindividual's SNP genotype, thereby enhancing and optimizing theeffectiveness of the therapy. Furthermore, the production of recombinantcells and transgenic animals containing particular SNPs/haplotypes alloweffective clinical design and testing of treatment compounds and dosageregimens. For example, transgenic animals can be produced that differonly in specific SNP alleles in a gene that is orthologous to a humandisease susceptibility gene.

Pharmacogenomic uses of the SNPs of the present invention provideseveral significant advantages for patient care, particularly inpredicting an individual's predisposition to psoriasis and in predictingan individual's responsiveness to a drug (particularly for treating orpreventing psoriasis). Pharmacogenomic characterization of anindividual, based on an individual's SNP genotype, can identify thoseindividuals unlikely to respond to treatment with a particularmedication and thereby allows physicians to avoid prescribing theineffective medication to those individuals. On the other hand, SNPgenotyping of an individual may enable physicians to select theappropriate medication and dosage regimen that will be most effectivebased on an individual's SNP genotype. This information increases aphysician's confidence in prescribing medications and motivates patientsto comply with their drug regimens. Furthermore, pharmacogenomics mayidentify patients predisposed to toxicity and adverse reactions toparticular drugs or drug dosages. Adverse drug reactions lead to morethan 100,000 avoidable deaths per year in the United States alone andtherefore represent a significant cause of hospitalization and death, aswell as a significant economic burden on the healthcare system (Pfost etal., Trends in Biotechnology, August 2000). Thus, pharmacogenomics basedon the SNPs disclosed herein has the potential to both save lives andreduce healthcare costs substantially.

Pharmacogenomics in general is discussed further in Rose et al.,“Pharmacogenetic analysis of clinically relevant genetic polymorphisms,”Methods Mol Med 85:225-37 (2003). Pharmacogenomics as it relates toAlzheimer's disease and other neurodegenerative disorders is discussedin Cacabelos, “Pharmacogenomics for the treatment of dementia,” Ann Med34(5):357-79 (2002); Maimone et al., “Pharmacogenomics ofneurodegenerative diseases,” Eur J Pharmacol 413(1):11-29 (February2001); and Poirier, “Apolipoprotein E: a pharmacogenetic target for thetreatment of Alzheimer's disease,” Mol Diagn 4(4):335-41 (December1999). Pharmacogenomics as it relates to cardiovascular disorders isdiscussed in Siest et al., “Pharmacogenomics of drugs affecting thecardiovascular system,” Clin Chem Lab Med 41(4):590-9 (April 2003);Mukherjee et al., “Pharmacogenomics in cardiovascular diseases,” ProgCardiovasc Dis 44(6):479-98 (May-June 2002); and Mooser et al.,“Cardiovascular pharmacogenetics in the SNP era,” J Thromb Haemost1(7):1398-402 (July 2003). Pharmacogenomics as it relates to cancer isdiscussed in McLeod et al., “Cancer pharmacogenomics: SNPs, chips, andthe individual patient,” Cancer Invest 21(4):630-40 (2003); and Watterset al., “Cancer pharmacogenomics: current and future applications,”Biochim Biophys Acta 1603(2):99-111 (March 2003).

Clinical Trials

In certain aspects of the invention, there are provided methods of usingthe SNPs disclosed herein to identify or stratify patient populationsfor clinical trials of a therapeutic, preventive, or diagnostic agent.

For instance, an aspect of the present invention includes selectingindividuals for clinical trials based on their SNP genotype, such asselecting individuals for inclusion in a clinical trial and/or assigningindividuals to a particular group within a clinical trial (e.g., an“arm” or “cohort” of the trial). For example, individuals with SNPgenotypes that indicate that they are likely to positively respond to adrug can be included in the trials, whereas those individuals whose SNPgenotypes indicate that they are less likely to or would not respond tothe drug, or who are at risk for suffering toxic effects or otheradverse reactions, can be excluded from the clinical trials. This notonly can improve the safety of clinical trials, but also can enhance thechances that the trial will demonstrate statistically significantefficacy.

Thus, certain embodiments of the invention provide methods forconducting a clinical trial of a therapeutic agent in which a human isselected for inclusion in the clinical trial and/or assigned to aparticular group within a clinical trial based on the presence orabsence of one or more SNPs disclosed herein. In certain embodiments,the therapeutic agent is an agent that targets IL12 and/or IL23, such asan anti-IL12 or anti-IL23 antibody.

In certain exemplary embodiments, SNPs of the invention can be used toselect individuals who are unlikely to respond positively to aparticular therapeutic agent (or class of therapeutic agents) based ontheir SNP genotype(s) to participate in a clinical trial of another typeof drug that may benefit them. Thus, in certain embodiments, the SNPs ofthe invention can be used to identify patient populations who do notadequately respond to current treatments and are therefore in need ofnew therapies. This not only benefits the patients themselves, but alsobenefits organizations such as pharmaceutical companies by enabling theidentification of populations that represent markets for new drugs, andenables the efficacy of these new drugs to be tested during clinicaltrials directly in individuals within these markets.

The SNP-containing nucleic acid molecules of the present invention arealso useful for monitoring the effectiveness of modulating compounds onthe expression or activity of a variant gene, or encoded product,particularly in a treatment regimen or in clinical trials. Thus, thegene expression pattern can serve as an indicator for the continuingeffectiveness of treatment with the compound, particularly withcompounds to which a patient can develop resistance, as well as anindicator for toxicities. The gene expression pattern can also serve asa marker indicative of a physiological response of the affected cells tothe compound. Accordingly, such monitoring would allow either increasedadministration of the compound or the administration of alternativecompounds to which the patient has not become resistant.

Furthermore, the SNPs of the present invention may have utility indetermining why certain previously developed drugs performed poorly inclinical trials and may help identify a subset of the population thatwould benefit from a drug that had previously performed poorly inclinical trials, thereby “rescuing” previously developed drugs, andenabling the drug to be made available to a particular psoriasis patientpopulation that can benefit from it.

Identification, Screening, and Use of Therapeutic Agents

The SNPs of the present invention also can be used to identify noveltherapeutic targets for psoriasis. For example, genes containing thedisease-associated variants (“variant genes”) or their products, as wellas genes or their products that are directly or indirectly regulated byor interacting with these variant genes or their products, can betargeted for the development of therapeutics that, for example, treatthe disease or prevent or delay disease onset. The therapeutics may becomposed of, for example, small molecules, proteins, protein fragmentsor peptides, antibodies, nucleic acids, or their derivatives or mimeticswhich modulate the functions or levels of the target genes or geneproducts.

The invention further provides methods for identifying a compound oragent that can be used to treat psoriasis. The SNPs disclosed herein areuseful as targets for the identification and/or development oftherapeutic agents. A method for identifying a therapeutic agent orcompound typically includes assaying the ability of the agent orcompound to modulate the activity and/or expression of a SNP-containingnucleic acid or the encoded product and thus identifying an agent or acompound that can be used to treat a disorder characterized by undesiredactivity or expression of the SNP-containing nucleic acid or the encodedproduct. The assays can be performed in cell-based and cell-freesystems. Cell-based assays can include cells naturally expressing thenucleic acid molecules of interest or recombinant cells geneticallyengineered to express certain nucleic acid molecules.

Variant gene expression in a psoriasis patient can include, for example,either expression of a SNP-containing nucleic acid sequence (forinstance, a gene that contains a SNP can be transcribed into an mRNAtranscript molecule containing the SNP, which can in turn be translatedinto a variant protein) or altered expression of a normal/wild-typenucleic acid sequence due to one or more SNPs (for instance, aregulatory/control region can contain a SNP that affects the level orpattern of expression of a normal transcript).

Assays for variant gene expression can involve direct assays of nucleicacid levels (e.g., mRNA levels), expressed protein levels, or ofcollateral compounds involved in a signal pathway. Further, theexpression of genes that are up- or down-regulated in response to thesignal pathway can also be assayed. In this embodiment, the regulatoryregions of these genes can be operably linked to a reporter gene such asluciferase.

Modulators of variant gene expression can be identified in a methodwherein, for example, a cell is contacted with a candidatecompound/agent and the expression of mRNA determined. The level ofexpression of mRNA in the presence of the candidate compound is comparedto the level of expression of mRNA in the absence of the candidatecompound. The candidate compound can then be identified as a modulatorof variant gene expression based on this comparison and be used to treata disorder such as psoriasis that is characterized by variant geneexpression (e.g., either expression of a SNP-containing nucleic acid oraltered expression of a normal/wild-type nucleic acid molecule due toone or more SNPs that affect expression of the nucleic acid molecule)due to one or more SNPs of the present invention. When expression ofmRNA is statistically significantly greater in the presence of thecandidate compound than in its absence, the candidate compound isidentified as a stimulator of nucleic acid expression. When nucleic acidexpression is statistically significantly less in the presence of thecandidate compound than in its absence, the candidate compound isidentified as an inhibitor of nucleic acid expression.

The invention further provides methods of treatment, with the SNP orassociated nucleic acid domain (e.g., catalytic domain,ligand/substrate-binding domain, regulatory/control region, etc.) orgene, or the encoded mRNA transcript, as a target, using a compoundidentified through drug screening as a gene modulator to modulatevariant nucleic acid expression. Modulation can include eitherup-regulation (i.e., activation or agonization) or down-regulation(i.e., suppression or antagonization) of nucleic acid expression.

Expression of mRNA transcripts and encoded proteins, either wild type orvariant, may be altered in individuals with a particular SNP allele in aregulatory/control element, such as a promoter or transcription factorbinding domain, that regulates expression. In this situation, methods oftreatment and compounds can be identified, as discussed herein, thatregulate or overcome the variant regulatory/control element, therebygenerating normal, or healthy, expression levels of either the wild typeor variant protein.

Pharmaceutical Compositions and Administration Thereof

Any of the psoriasis-associated proteins, and encoding nucleic acidmolecules, disclosed herein can be used as therapeutic targets (ordirectly used themselves as therapeutic compounds) for treating orpreventing psoriasis or related pathologies, and the present disclosureenables therapeutic compounds (e.g., small molecules, antibodies,therapeutic proteins, RNAi and antisense molecules, etc.) to bedeveloped that target (or are comprised of) any of these therapeutictargets.

In general, a therapeutic compound will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the therapeutic compound of this invention, i.e., the activeingredient, will depend upon numerous factors such as the severity ofthe disease to be treated, the age and relative health of the subject,the potency of the compound used, the route and form of administration,and other factors.

Therapeutically effective amounts of therapeutic compounds may rangefrom, for example, approximately 0.01-50 mg per kilogram body weight ofthe recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as anexample, for administration to a 70-kg person, the dosage range wouldmost preferably be about 7 mg to 1.4 g per day.

In general, therapeutic compounds will be administered as pharmaceuticalcompositions by any one of the following routes: oral, systemic (e.g.,transdermal, intranasal, or by suppository), or parenteral (e.g.,intramuscular, intravenous, or subcutaneous) administration. Thepreferred manner of administration is oral or parenteral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Oral compositions can take the form of tablets,pills, capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors such as the mode ofdrug administration (e.g., for oral administration, formulations in theform of tablets, pills, or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area, i.e., decreasing particlesize. For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a cross-linked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

Pharmaceutical compositions are comprised of, in general, a therapeuticcompound in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the therapeuticcompound. Such excipients may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences 18^(th) ed., E. W.Martin, ed., Mack Publishing Company (1990).

The amount of the therapeutic compound in a formulation can vary withinthe full range employed by those skilled in the art. Typically, theformulation will contain, on a weight percent (wt %) basis, from about0.01-99.99 wt % of the therapeutic compound based on the totalformulation, with the balance being one or more suitable pharmaceuticalexcipients. Preferably, the compound is present at a level of about1-80% wt.

Therapeutic compounds can be administered alone or in combination withother therapeutic compounds or in combination with one or more otheractive ingredient(s). For example, an inhibitor or stimulator of apsoriasis-associated protein can be administered in combination withanother agent that inhibits or stimulates the activity of the same or adifferent psoriasis-associated protein to thereby counteract the effectsof psoriasis.

For further information regarding pharmacology, see Current Protocols inPharmacology, John Wiley & Sons, Inc., N.Y.

Nucleic Acid-Based Therapeutic Agents

The SNP-containing nucleic acid molecules disclosed herein, and theircomplementary nucleic acid molecules, may be used as antisenseconstructs to control gene expression in cells, tissues, and organisms.Antisense technology is well established in the art and extensivelyreviewed in Antisense Drug Technology: Principles, Strategies, andApplications, Crooke, ed., Marcel Dekker, Inc., N.Y. (2001). Anantisense nucleic acid molecule is generally designed to becomplementary to a region of mRNA expressed by a gene so that theantisense molecule hybridizes to the mRNA and thereby blocks translationof mRNA into protein. Various classes of antisense oligonucleotides areused in the art, two of which are cleavers and blockers. Cleavers, bybinding to target RNAs, activate intracellular nucleases (e.g., RNaseHor RNase L) that cleave the target RNA. Blockers, which also bind totarget RNAs, inhibit protein translation through steric hindrance ofribosomes. Exemplary blockers include peptide nucleic acids,morpholinos, locked nucleic acids, and methylphosphonates. See, e.g.,Thompson, Drug Discovery Today 7(17): 912-917 (2002). Antisenseoligonucleotides are directly useful as therapeutic agents, and are alsouseful for determining and validating gene function (e.g., in geneknock-out or knock-down experiments).

Antisense technology is further reviewed in: Layery et al., “Antisenseand RNAi: powerful tools in drug target discovery and validation,” CurrOpin Drug Discov Devel 6(4):561-9 (July 2003); Stephens et al.,“Antisense oligonucleotide therapy in cancer,” Curr Opin Mol Ther5(2):118-22 (April 2003); Kurreck, “Antisense technologies. Improvementthrough novel chemical modifications,” Eur J Biochem 270(8):1628-44(April 2003); Dias et al., “Antisense oligonucleotides: basic conceptsand mechanisms,” Mol Cancer Ther 1(5):347-55 (March 2002); Chen,“Clinical development of antisense oligonucleotides as anti-cancertherapeutics,” Methods Mol Med 75:621-36 (2003); Wang et al., “Antisenseanticancer oligonucleotide therapeutics,” Curr Cancer Drug Targets1(3):177-96 (November 2001); and Bennett, “Efficiency of antisenseoligonucleotide drug discovery,” Antisense Nucleic Acid Drug Dev12(3):215-24 (June 2002).

The SNPs of the present invention are particularly useful for designingantisense reagents that are specific for particular nucleic acidvariants. Based on the SNP information disclosed herein, antisenseoligonucleotides can be produced that specifically target mRNA moleculesthat contain one or more particular SNP nucleotides. In this manner,expression of mRNA molecules that contain one or more undesiredpolymorphisms (e.g., SNP nucleotides that lead to a defective proteinsuch as an amino acid substitution in a catalytic domain) can beinhibited or completely blocked. Thus, antisense oligonucleotides can beused to specifically bind a particular polymorphic form (e.g., a SNPallele that encodes a defective protein), thereby inhibiting translationof this form, but which do not bind an alternative polymorphic form(e.g., an alternative SNP nucleotide that encodes a protein havingnormal function).

Antisense molecules can be used to inactivate mRNA in order to inhibitgene expression and production of defective proteins. Accordingly, thesemolecules can be used to treat a disorder, such as psoriasis,characterized by abnormal or undesired gene expression or expression ofcertain defective proteins. This technique can involve cleavage by meansof ribozymes containing nucleotide sequences complementary to one ormore regions in the mRNA that attenuate the ability of the mRNA to betranslated. Possible mRNA regions include, for example, protein-codingregions and particularly protein-coding regions corresponding tocatalytic activities, substrate/ligand binding, or other functionalactivities of a protein.

The SNPs of the present invention are also useful for designing RNAinterference reagents that specifically target nucleic acid moleculeshaving particular SNP variants. RNA interference (RNAi), also referredto as gene silencing, is based on using double-stranded RNA (dsRNA)molecules to turn genes off. When introduced into a cell, dsRNAs areprocessed by the cell into short fragments (generally about 21, 22, or23 nucleotides in length) known as small interfering RNAs (siRNAs) whichthe cell uses in a sequence-specific manner to recognize and destroycomplementary RNAs. Thompson, Drug Discovery Today 7(17): 912-917(2002). Accordingly, an aspect of the present invention specificallycontemplates isolated nucleic acid molecules that are about 18-26nucleotides in length, preferably 19-25 nucleotides in length, and morepreferably 20, 21, 22, or 23 nucleotides in length, and the use of thesenucleic acid molecules for RNAi. Because RNAi molecules, includingsiRNAs, act in a sequence-specific manner, the SNPs of the presentinvention can be used to design RNAi reagents that recognize and destroynucleic acid molecules having specific SNP alleles/nucleotides (such asdeleterious alleles that lead to the production of defective proteins),while not affecting nucleic acid molecules having alternative SNPalleles (such as alleles that encode proteins having normal function).As with antisense reagents, RNAi reagents may be directly useful astherapeutic agents (e.g., for turning off defective, disease-causinggenes), and are also useful for characterizing and validating genefunction (e.g., in gene knock-out or knock-down experiments).

The following references provide a further review of RNAi: Reynolds etal., “Rational siRNA design for RNA interference,” Nat Biotechnol22(3):326-30 (March 2004); Epub Feb. 1, 2004; Chi et al., “Genomewideview of gene silencing by small interfering RNAs,” PNAS100(11):6343-6346 (2003); Vickers et al., “Efficient Reduction of TargetRNAs by Small Interfering RNA and RNase H-dependent Antisense Agents,” JBiol Chem 278:7108-7118 (2003); Agami, “RNAi and related mechanisms andtheir potential use for therapy,” Curr Opin Chem Biol 6(6):829-34(December 2002); Layery et al., “Antisense and RNAi: powerful tools indrug target discovery and validation,” Curr Opin Drug Discov Devel6(4):561-9 (July 2003); Shi, “Mammalian RNAi for the masses,” TrendsGenet 19(1):9-12 (January 2003); Shuey et al., “RNAi: gene-silencing intherapeutic intervention,” Drug Discovery Today 7(20):1040-1046 (October2002); McManus et al., Nat Rev Genet 3(10):737-47 (October 2002); Xia etal., Nat Biotechnol 20(10):1006-10 (October 2002); Plasterk et al., CurrOpin Genet Dev 10(5):562-7 (October 2000); Bosher et al., Nat Cell Biol2(2):E31-6 (February 2000); and Hunter, Curr Biol 17; 9(12):R440-2 (June1999).

Other Therapeutic Aspects

SNPs have many important uses in drug discovery, screening, anddevelopment, and thus the SNPs of the present invention are useful forimproving many different aspects of the drug development process.

For example, a high probability exists that, for any gene/proteinselected as a potential drug target, variants of that gene/protein willexist in a patient population. Thus, determining the impact ofgene/protein variants on the selection and delivery of a therapeuticagent should be an integral aspect of the drug discovery and developmentprocess. Jazwinska, A Trends Guide to Genetic Variation and GenomicMedicine S30-S36 (March 2002).

Knowledge of variants (e.g., SNPs and any corresponding amino acidpolymorphisms) of a particular therapeutic target (e.g., a gene, mRNAtranscript, or protein) enables parallel screening of the variants inorder to identify therapeutic candidates (e.g., small moleculecompounds, antibodies, antisense or RNAi nucleic acid compounds, etc.)that demonstrate efficacy across variants. Rothberg, Nat Biotechnol19(3):209-11 (March 2001). Such therapeutic candidates would be expectedto show equal efficacy across a larger segment of the patientpopulation, thereby leading to a larger potential market for thetherapeutic candidate.

Furthermore, identifying variants of a potential therapeutic targetenables the most common form of the target to be used for selection oftherapeutic candidates, thereby helping to ensure that the experimentalactivity that is observed for the selected candidates reflects the realactivity expected in the largest proportion of a patient population.Jazwinska, A Trends Guide to Genetic Variation and Genomic MedicineS30-S36 (March 2002).

Additionally, screening therapeutic candidates against all knownvariants of a target can enable the early identification of potentialtoxicities and adverse reactions relating to particular variants. Forexample, variability in drug absorption, distribution, metabolism andexcretion (ADME) caused by, for example, SNPs in therapeutic targets ordrug metabolizing genes, can be identified, and this information can beutilized during the drug development process to minimize variability indrug disposition and develop therapeutic agents that are safer across awider range of a patient population. The SNPs of the present invention,including the variant proteins and encoding polymorphic nucleic acidmolecules provided in Tables 1 and 2, are useful in conjunction with avariety of toxicology methods established in the art, such as those setforth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

Furthermore, therapeutic agents that target any art-known proteins (ornucleic acid molecules, either RNA or DNA) may cross-react with thevariant proteins (or polymorphic nucleic acid molecules) disclosed inTable 1, thereby significantly affecting the pharmacokinetic propertiesof the drug. Consequently, the protein variants and the SNP-containingnucleic acid molecules disclosed in Tables 1 and 2 are useful indeveloping, screening, and evaluating therapeutic agents that targetcorresponding art-known protein forms (or nucleic acid molecules).Additionally, as discussed above, knowledge of all polymorphic forms ofa particular drug target enables the design of therapeutic agents thatare effective against most or all such polymorphic forms of the drugtarget.

A subject suffering from a pathological condition ascribed to a SNP,such as psoriasis, may be treated so as to correct the genetic defect.See Kren et al., Proc Natl Acad Sci USA 96:10349-10354 (1999). Such asubject can be identified by any method that can detect the polymorphismin a biological sample drawn from the subject. Such a genetic defect maybe permanently corrected by administering to such a subject a nucleicacid fragment incorporating a repair sequence that supplies thenormal/wild-type nucleotide at the position of the SNP. Thissite-specific repair sequence can encompass an RNA/DNA oligonucleotidethat operates to promote endogenous repair of a subject's genomic DNA.The site-specific repair sequence is administered in an appropriatevehicle, such as a complex with polyethylenimine, encapsulated inanionic liposomes, a viral vector such as an adenovirus, or otherpharmaceutical composition that promotes intracellular uptake of theadministered nucleic acid. A genetic defect leading to an inbornpathology may then be overcome, as the chimeric oligonucleotides induceincorporation of the normal sequence into the subject's genome. Uponincorporation, the normal gene product is expressed, and the replacementis propagated, thereby engendering a permanent repair and therapeuticenhancement of the clinical condition of the subject.

In cases in which a cSNP results in a variant protein that is ascribedto be the cause of, or a contributing factor to, a pathologicalcondition, a method of treating such a condition can includeadministering to a subject experiencing the pathology thewild-type/normal cognate of the variant protein. Once administered in aneffective dosing regimen, the wild-type cognate provides complementationor remediation of the pathological condition.

Human Identification Applications

In addition to their diagnostic, therapeutic, and preventive uses inpsoriasis and related pathologies, the SNPs provided by the presentinvention are also useful as human identification markers for suchapplications as forensics, paternity testing, and biometrics. See, e.g.,Gill, “An assessment of the utility of single nucleotide polymorphisms(SNPs) for forensic purposes,” Int J Legal Med 114(4-5):204-10 (2001).Genetic variations in the nucleic acid sequences between individuals canbe used as genetic markers to identify individuals and to associate abiological sample with an individual. Determination of which nucleotidesoccupy a set of SNP positions in an individual identifies a set of SNPmarkers that distinguishes the individual. The more SNP positions thatare analyzed, the lower the probability that the set of SNPs in oneindividual is the same as that in an unrelated individual. Preferably,if multiple sites are analyzed, the sites are unlinked (i.e., inheritedindependently). Thus, preferred sets of SNPs can be selected from amongthe SNPs disclosed herein, which may include SNPs on differentchromosomes, SNPs on different chromosome arms, and/or SNPs that aredispersed over substantial distances along the same chromosome arm.

Furthermore, among the SNPs disclosed herein, preferred SNPs for use incertain forensic/human identification applications include SNPs locatedat degenerate codon positions (i.e., the third position in certaincodons which can be one of two or more alternative nucleotides and stillencode the same amino acid), since these SNPs do not affect the encodedprotein. SNPs that do not affect the encoded protein are expected to beunder less selective pressure and are therefore expected to be morepolymorphic in a population, which is typically an advantage forforensic/human identification applications. However, for certainforensics/human identification applications, such as predictingphenotypic characteristics (e.g., inferring ancestry or inferring one ormore physical characteristics of an individual) from a DNA sample, itmay be desirable to utilize SNPs that affect the encoded protein.

For many of the SNPs disclosed in Tables 1 and 2 (which are identifiedas “Applera” SNP source), Tables 1 and 2 provide SNP allele frequenciesobtained by re-sequencing the DNA of chromosomes from 39 individuals(Tables 1 and 2 also provide allele frequency information for “Celera”source SNPs and, where available, public SNPs from dbEST, HGBASE, and/orHGMD). The allele frequencies provided in Tables 1 and 2 enable theseSNPs to be readily used for human identification applications. Althoughany SNP disclosed in Table 1 and/or Table 2 could be used for humanidentification, the closer that the frequency of the minor allele at aparticular SNP site is to 50%, the greater the ability of that SNP todiscriminate between different individuals in a population since itbecomes increasingly likely that two randomly selected individuals wouldhave different alleles at that SNP site. Using the SNP allelefrequencies provided in Tables 1 and 2, one of ordinary skill in the artcould readily select a subset of SNPs for which the frequency of theminor allele is, for example, at least 1%, 2%, 5%, 10%, 20%, 25%, 30%,40%, 45%, or 50%, or any other frequency in-between. Thus, since Tables1 and 2 provide allele frequencies based on the re-sequencing of thechromosomes from 39 individuals, a subset of SNPs could readily beselected for human identification in which the total allele count of theminor allele at a particular SNP site is, for example, at least 1, 2, 4,8, 10, 16, 20, 24, 30, 32, 36, 38, 39, 40, or any other numberin-between.

Furthermore, Tables 1 and 2 also provide population group(interchangeably referred to herein as ethnic or racial groups)information coupled with the extensive allele frequency information. Forexample, the group of 39 individuals whose DNA was re-sequenced wasmade-up of 20 Caucasians and 19 African-Americans. This population groupinformation enables further refinement of SNP selection for humanidentification. For example, preferred SNPs for human identification canbe selected from Tables 1 and 2 that have similar allele frequencies inboth the Caucasian and African-American populations; thus, for example,SNPs can be selected that have equally high discriminatory power in bothpopulations. Alternatively, SNPs can be selected for which there is astatistically significant difference in allele frequencies between theCaucasian and African-American populations (as an extreme example, aparticular allele may be observed only in either the Caucasian or theAfrican-American population group but not observed in the otherpopulation group); such SNPs are useful, for example, for predicting therace/ethnicity of an unknown perpetrator from a biological sample suchas a hair or blood stain recovered at a crime scene. For a discussion ofusing SNPs to predict ancestry from a DNA sample, including statisticalmethods, see Frudakis et al., “A Classifier for the SNP-Based Inferenceof Ancestry,” Journal of Forensic Sciences 48(4):771-782 (2003).

SNPs have numerous advantages over other types of polymorphic markers,such as short tandem repeats (STRs). For example, SNPs can be easilyscored and are amenable to automation, making SNPs the markers of choicefor large-scale forensic databases. SNPs are found in much greaterabundance throughout the genome than repeat polymorphisms. Populationfrequencies of two polymorphic forms can usually be determined withgreater accuracy than those of multiple polymorphic forms atmulti-allelic loci. SNPs are mutationally more stable than repeatpolymorphisms. SNPs are not susceptible to artifacts such as stutterbands that can hinder analysis. Stutter bands are frequently encounteredwhen analyzing repeat polymorphisms, and are particularly troublesomewhen analyzing samples such as crime scene samples that may containmixtures of DNA from multiple sources. Another significant advantage ofSNP markers over STR markers is the much shorter length of nucleic acidneeded to score a SNP. For example, STR markers are generally severalhundred base pairs in length. A SNP, on the other hand, comprises asingle nucleotide, and generally a short conserved region on either sideof the SNP position for primer and/or probe binding. This makes SNPsmore amenable to typing in highly degraded or aged biological samplesthat are frequently encountered in forensic casework in which DNA may befragmented into short pieces.

SNPs also are not subject to microvariant and “off-ladder” allelesfrequently encountered when analyzing STR loci. Microvariants aredeletions or insertions within a repeat unit that change the size of theamplified DNA product so that the amplified product does not migrate atthe same rate as reference alleles with normal sized repeat units. Whenseparated by size, such as by electrophoresis on a polyacrylamide gel,microvariants do not align with a reference allelic ladder of standardsized repeat units, but rather migrate between the reference alleles.The reference allelic ladder is used for precise sizing of alleles forallele classification; therefore alleles that do not align with thereference allelic ladder lead to substantial analysis problems.Furthermore, when analyzing multi-allelic repeat polymorphisms,occasionally an allele is found that consists of more or less repeatunits than has been previously seen in the population, or more or lessrepeat alleles than are included in a reference allelic ladder. Thesealleles will migrate outside the size range of known alleles in areference allelic ladder, and therefore are referred to as “off-ladder”alleles. In extreme cases, the allele may contain so few or so manyrepeats that it migrates well out of the range of the reference allelicladder. In this situation, the allele may not even be observed, or, withmultiplex analysis, it may migrate within or close to the size range foranother locus, further confounding analysis.

SNP analysis avoids the problems of microvariants and off-ladder allelesencountered in STR analysis. Importantly, microvariants and off-ladderalleles may provide significant problems, and may be completely missed,when using analysis methods such as oligonucleotide hybridizationarrays, which utilize oligonucleotide probes specific for certain knownalleles. Furthermore, off-ladder alleles and microvariants encounteredwith STR analysis, even when correctly typed, may lead to improperstatistical analysis, since their frequencies in the population aregenerally unknown or poorly characterized, and therefore the statisticalsignificance of a matching genotype may be questionable. All theseadvantages of SNP analysis are considerable in light of the consequencesof most DNA identification cases, which may lead to life imprisonmentfor an individual, or re-association of remains to the family of adeceased individual.

DNA can be isolated from biological samples such as blood, bone, hair,saliva, or semen, and compared with the DNA from a reference source atparticular SNP positions. Multiple SNP markers can be assayedsimultaneously in order to increase the power of discrimination and thestatistical significance of a matching genotype. For example,oligonucleotide arrays can be used to genotype a large number of SNPssimultaneously. The SNPs provided by the present invention can beassayed in combination with other polymorphic genetic markers, such asother SNPs known in the art or STRs, in order to identify an individualor to associate an individual with a particular biological sample.

Furthermore, the SNPs provided by the present invention can be genotypedfor inclusion in a database of DNA genotypes, for example, a criminalDNA databank such as the FBI's Combined DNA Index System (CODIS)database. A genotype obtained from a biological sample of unknown sourcecan then be queried against the database to find a matching genotype,with the SNPs of the present invention providing nucleotide positions atwhich to compare the known and unknown DNA sequences for identity.Accordingly, the present invention provides a database comprising novelSNPs or SNP alleles of the present invention (e.g., the database cancomprise information indicating which alleles are possessed byindividual members of a population at one or more novel SNP sites of thepresent invention), such as for use in forensics, biometrics, or otherhuman identification applications. Such a database typically comprises acomputer-based system in which the SNPs or SNP alleles of the presentinvention are recorded on a computer readable medium.

The SNPs of the present invention can also be assayed for use inpaternity testing. The object of paternity testing is usually todetermine whether a male is the father of a child. In most cases, themother of the child is known and thus, the mother's contribution to thechild's genotype can be traced. Paternity testing investigates whetherthe part of the child's genotype not attributable to the mother isconsistent with that of the putative father. Paternity testing can beperformed by analyzing sets of polymorphisms in the putative father andthe child, with the SNPs of the present invention providing nucleotidepositions at which to compare the putative father's and child's DNAsequences for identity. If the set of polymorphisms in the childattributable to the father does not match the set of polymorphisms ofthe putative father, it can be concluded, barring experimental error,that the putative father is not the father of the child. If the set ofpolymorphisms in the child attributable to the father match the set ofpolymorphisms of the putative father, a statistical calculation can beperformed to determine the probability of coincidental match, and aconclusion drawn as to the likelihood that the putative father is thetrue biological father of the child.

In addition to paternity testing, SNPs are also useful for other typesof kinship testing, such as for verifying familial relationships forimmigration purposes, or for cases in which an individual alleges to berelated to a deceased individual in order to claim an inheritance fromthe deceased individual, etc. For further information regarding theutility of SNPs for paternity testing and other types of kinshiptesting, including methods for statistical analysis, see Krawczak,“Informativity assessment for biallelic single nucleotidepolymorphisms,” Electrophoresis 20(8):1676-81 (June 1999).

The use of the SNPs of the present invention for human identificationfurther extends to various authentication systems, commonly referred toas biometric systems, which typically convert physical characteristicsof humans (or other organisms) into digital data. Biometric systemsinclude various technological devices that measure such uniqueanatomical or physiological characteristics as finger, thumb, or palmprints; hand geometry; vein patterning on the back of the hand; bloodvessel patterning of the retina and color and texture of the iris;facial characteristics; voice patterns; signature and typing dynamics;and DNA. Such physiological measurements can be used to verify identityand, for example, restrict or allow access based on the identification.Examples of applications for biometrics include physical area security,computer and network security, aircraft passenger check-in and boarding,financial transactions, medical records access, government benefitdistribution, voting, law enforcement, passports, visas and immigration,prisons, various military applications, and for restricting access toexpensive or dangerous items, such as automobiles or guns. See, forexample, O'Connor, Stanford Technology Law Review, and U.S. Pat. No.6,119,096.

Groups of SNPs, particularly the SNPs provided by the present invention,can be typed to uniquely identify an individual for biometricapplications such as those described above. Such SNP typing can readilybe accomplished using, for example, DNA chips/arrays. Preferably, aminimally invasive means for obtaining a DNA sample is utilized. Forexample, PCR amplification enables sufficient quantities of DNA foranalysis to be obtained from buccal swabs or fingerprints, which containDNA-containing skin cells and oils that are naturally transferred duringcontact.

Further information regarding techniques for using SNPs inforensic/human identification applications can be found, for example, inCurrent Protocols in Human Genetics 14.1-14.7, John Wiley & Sons, N.Y.(2002).

Variant Proteins, Antibodies, Vectors, Host Cells, & Uses Thereof

Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

The present invention provides SNP-containing nucleic acid molecules,many of which encode proteins having variant amino acid sequences ascompared to the art-known (i.e., wild-type) proteins. Amino acidsequences encoded by the polymorphic nucleic acid molecules of thepresent invention are referred to as SEQ ID NOS:3-4 in Table 1 andprovided in the Sequence Listing. These variants will generally bereferred to herein as variant proteins/peptides/polypeptides, orpolymorphic proteins/peptides/polypeptides of the present invention. Theterms “protein,” “peptide,” and “polypeptide” are used hereininterchangeably.

A variant protein of the present invention may be encoded by, forexample, a nonsynonymous nucleotide substitution at any one of the cSNPpositions disclosed herein. In addition, variant proteins may alsoinclude proteins whose expression, structure, and/or function is alteredby a SNP disclosed herein, such as a SNP that creates or destroys a stopcodon, a SNP that affects splicing, and a SNP in control/regulatoryelements, e.g. promoters, enhancers, or transcription factor bindingdomains.

As used herein, a protein or peptide is said to be “isolated” or“purified” when it is substantially free of cellular material orchemical precursors or other chemicals. The variant proteins of thepresent invention can be purified to homogeneity or other lower degreesof purity. The level of purification will be based on the intended use.The key feature is that the preparation allows for the desired functionof the variant protein, even if in the presence of considerable amountsof other components.

As used herein, “substantially free of cellular material” includespreparations of the variant protein having less than about 30% (by dryweight) other proteins (i.e., contaminating protein), less than about20% other proteins, less than about 10% other proteins, or less thanabout 5% other proteins. When the variant protein is recombinantlyproduced, it can also be substantially free of culture medium, i.e.,culture medium represents less than about 20% of the volume of theprotein preparation.

The language “substantially free of chemical precursors or otherchemicals” includes preparations of the variant protein in which it isseparated from chemical precursors or other chemicals that are involvedin its synthesis. In one embodiment, the language “substantially free ofchemical precursors or other chemicals” includes preparations of thevariant protein having less than about 30% (by dry weight) chemicalprecursors or other chemicals, less than about 20% chemical precursorsor other chemicals, less than about 10% chemical precursors or otherchemicals, or less than about 5% chemical precursors or other chemicals.

An isolated variant protein may be purified from cells that naturallyexpress it, purified from cells that have been altered to express it(recombinant host cells), or synthesized using known protein synthesismethods. For example, a nucleic acid molecule containing SNP(s) encodingthe variant protein can be cloned into an expression vector, theexpression vector introduced into a host cell, and the variant proteinexpressed in the host cell. The variant protein can then be isolatedfrom the cells by any appropriate purification scheme using standardprotein purification techniques. Examples of these techniques aredescribed in detail below. Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The present invention provides isolated variant proteins that comprise,consist of or consist essentially of amino acid sequences that containone or more variant amino acids encoded by one or more codons thatcontain a SNP of the present invention.

Accordingly, the present invention provides variant proteins thatconsist of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists of an amino acid sequencewhen the amino acid sequence is the entire amino acid sequence of theprotein.

The present invention further provides variant proteins that consistessentially of amino acid sequences that contain one or more amino acidpolymorphisms (or truncations or extensions due to creation ordestruction of a stop codon, respectively) encoded by the SNPs providedin Table 1 and/or Table 2. A protein consists essentially of an aminoacid sequence when such an amino acid sequence is present with only afew additional amino acid residues in the final protein.

The present invention further provides variant proteins that compriseamino acid sequences that contain one or more amino acid polymorphisms(or truncations or extensions due to creation or destruction of a stopcodon, respectively) encoded by the SNPs provided in Table 1 and/orTable 2. A protein comprises an amino acid sequence when the amino acidsequence is at least part of the final amino acid sequence of theprotein. In such a fashion, the protein may contain only the variantamino acid sequence or have additional amino acid residues, such as acontiguous encoded sequence that is naturally associated with it orheterologous amino acid residues. Such a protein can have a fewadditional amino acid residues or can comprise many more additionalamino acids. A brief description of how various types of these proteinscan be made and isolated is provided below.

The variant proteins of the present invention can be attached toheterologous sequences to form chimeric or fusion proteins. Suchchimeric and fusion proteins comprise a variant protein operativelylinked to a heterologous protein having an amino acid sequence notsubstantially homologous to the variant protein. “Operatively linked”indicates that the coding sequences for the variant protein and theheterologous protein are ligated in-frame. The heterologous protein canbe fused to the N-terminus or C-terminus of the variant protein. Inanother embodiment, the fusion protein is encoded by a fusionpolynucleotide that is synthesized by conventional techniques includingautomated DNA synthesizers. Alternatively, PCR amplification of genefragments can be carried out using anchor primers which give rise tocomplementary overhangs between two consecutive gene fragments which cansubsequently be annealed and re-amplified to generate a chimeric genesequence. See Ausubel et al., Current Protocols in Molecular Biology(1992). Moreover, many expression vectors are commercially availablethat already encode a fusion moiety (e.g., a GST protein). A variantprotein-encoding nucleic acid can be cloned into such an expressionvector such that the fusion moiety is linked in-frame to the variantprotein.

In many uses, the fusion protein does not affect the activity of thevariant protein. The fusion protein can include, but is not limited to,enzymatic fusion proteins, for example, beta-galactosidase fusions,yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-taggedand Ig fusions. Such fusion proteins, particularly poly-His fusions, canfacilitate their purification following recombinant expression. Incertain host cells (e.g., mammalian host cells), expression and/orsecretion of a protein can be increased by using a heterologous signalsequence. Fusion proteins are further described in, for example, Terpe,“Overview of tag protein fusions: from molecular and biochemicalfundamentals to commercial systems,” Appl Microbiol Biotechnol60(5):523-33 (January 2003); Epub Nov. 7, 2002; Graddis et al.,“Designing proteins that work using recombinant technologies,” CurrPharm Biotechnol 3(4):285-97 (December 2002); and Nilsson et al.,“Affinity fusion strategies for detection, purification, andimmobilization of recombinant proteins,” Protein Expr Purif 11(1):1-16(October 1997).

In certain embodiments, novel compositions of the present invention alsorelate to further obvious variants of the variant polypeptides of thepresent invention, such as naturally-occurring mature forms (e.g.,allelic variants), non-naturally occurring recombinantly-derivedvariants, and orthologs and paralogs of such proteins that sharesequence homology. Such variants can readily be generated usingart-known techniques in the fields of recombinant nucleic acidtechnology and protein biochemistry.

Further variants of the variant polypeptides disclosed in Table 1 cancomprise an amino acid sequence that shares at least 70-80%, 80-85%,85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identitywith an amino acid sequence disclosed in Table 1 (or a fragment thereof)and that includes a novel amino acid residue (allele) disclosed in Table1 (which is encoded by a novel SNP allele). Thus, an aspect of thepresent invention that is specifically contemplated are polypeptidesthat have a certain degree of sequence variation compared with thepolypeptide sequences shown in Table 1, but that contain a novel aminoacid residue (allele) encoded by a novel SNP allele disclosed herein. Inother words, as long as a polypeptide contains a novel amino acidresidue disclosed herein, other portions of the polypeptide that flankthe novel amino acid residue can vary to some degree from thepolypeptide sequences shown in Table 1.

Full-length pre-processed forms, as well as mature processed forms, ofproteins that comprise one of the amino acid sequences disclosed hereincan readily be identified as having complete sequence identity to one ofthe variant proteins of the present invention as well as being encodedby the same genetic locus as the variant proteins provided herein.

Orthologs of a variant peptide can readily be identified as having somedegree of significant sequence homology/identity to at least a portionof a variant peptide as well as being encoded by a gene from anotherorganism. Preferred orthologs will be isolated from non-human mammals,preferably primates, for the development of human therapeutic targetsand agents. Such orthologs can be encoded by a nucleic acid sequencethat hybridizes to a variant peptide-encoding nucleic acid moleculeunder moderate to stringent conditions depending on the degree ofrelatedness of the two organisms yielding the homologous proteins.

Variant proteins include, but are not limited to, proteins containingdeletions, additions and substitutions in the amino acid sequence causedby the SNPs of the present invention. One class of substitutions isconserved amino acid substitutions in which a given amino acid in apolypeptide is substituted for another amino acid of likecharacteristics. Typical conservative substitutions are replacements,one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile;interchange of the hydroxyl residues Ser and Thr; exchange of the acidicresidues Asp and Glu; substitution between the amide residues Asn andGln; exchange of the basic residues Lys and Arg; and replacements amongthe aromatic residues Phe and Tyr. Guidance concerning which amino acidchanges are likely to be phenotypically silent are found, for example,in Bowie et al., Science 247:1306-1310 (1990).

Variant proteins can be fully functional or can lack function in one ormore activities, e.g. ability to bind another molecule, ability tocatalyze a substrate, ability to mediate signaling, etc. Fullyfunctional variants typically contain only conservative variations orvariations in non-critical residues or in non-critical regions.Functional variants can also contain substitution of similar amino acidsthat result in no change or an insignificant change in function.Alternatively, such substitutions may positively or negatively affectfunction to some degree. Non-functional variants typically contain oneor more non-conservative amino acid substitutions, deletions,insertions, inversions, truncations or extensions, or a substitution,insertion, inversion, or deletion of a critical residue or in a criticalregion.

Amino acids that are essential for function of a protein can beidentified by methods known in the art, such as site-directedmutagenesis or alanine-scanning mutagenesis, particularly using theamino acid sequence and polymorphism information provided in Table 1.Cunningham et al., Science 244:1081-1085 (1989). The latter procedureintroduces single alanine mutations at every residue in the molecule.The resulting mutant molecules are then tested for biological activitysuch as enzyme activity or in assays such as an in vitro proliferativeactivity. Sites that are critical for binding partner/substrate bindingcan also be determined by structural analysis such as crystallization,nuclear magnetic resonance or photoaffinity labeling. Smith et al., JMol Biol 224:899-904 (1992); de Vos et al., Science 255:306-312 (1992).

Polypeptides can contain amino acids other than the 20 amino acidscommonly referred to as the 20 naturally occurring amino acids. Further,many amino acids, including the terminal amino acids, may be modified bynatural processes, such as processing and other post-translationalmodifications, or by chemical modification techniques well known in theart. Accordingly, the variant proteins of the present invention alsoencompass derivatives or analogs in which a substituted amino acidresidue is not one encoded by the genetic code, in which a substituentgroup is included, in which the mature polypeptide is fused with anothercompound, such as a compound to increase the half-life of thepolypeptide (e.g., polyethylene glycol), or in which additional aminoacids are fused to the mature polypeptide, such as a leader or secretorysequence or a sequence for purification of the mature polypeptide or apro-protein sequence.

Known protein modifications include, but are not limited to,acetylation, acylation, ADP-ribosylation, amidation, covalent attachmentof flavin, covalent attachment of a heme moiety, covalent attachment ofa nucleotide or nucleotide derivative, covalent attachment of a lipid orlipid derivative, covalent attachment of phosphotidylinositol,cross-linking, cyclization, disulfide bond formation, demethylation,formation of covalent crosslinks, formation of cystine, formation ofpyroglutamate, formylation, gamma carboxylation, glycosylation, GPIanchor formation, hydroxylation, iodination, methylation,myristoylation, oxidation, proteolytic processing, phosphorylation,prenylation, racemization, selenoylation, sulfation, transfer-RNAmediated addition of amino acids to proteins such as arginylation, andubiquitination.

Such protein modifications are well known to those of skill in the artand have been described in great detail in the scientific literature.Particularly common modifications, for example glycosylation, lipidattachment, sulfation, gamma-carboxylation of glutamic acid residues,hydroxylation and ADP-ribosylation, are described in most basic texts,such as Proteins—Structure and Molecular Properties 2nd Ed., T. E.Creighton, W.H. Freeman and Company, N.Y. (1993); F. Wold,Posttranslational Covalent Modification of Proteins 1-12, B. C. Johnson,ed., Academic Press, N.Y. (1983); Seifter et al., Meth Enzymol182:626-646 (1990); and Rattan et al., Ann NY Acad Sci 663:48-62 (1992).

The present invention further provides fragments of the variant proteinsin which the fragments contain one or more amino acid sequencevariations (e.g., substitutions, or truncations or extensions due tocreation or destruction of a stop codon) encoded by one or more SNPsdisclosed herein. The fragments to which the invention pertains,however, are not to be construed as encompassing fragments that havebeen disclosed in the prior art before the present invention.

As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14,16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or morecontiguous amino acid residues from a variant protein, wherein at leastone amino acid residue is affected by a SNP of the present invention,e.g., a variant amino acid residue encoded by a nonsynonymous nucleotidesubstitution at a cSNP position provided by the present invention. Thevariant amino acid encoded by a cSNP may occupy any residue positionalong the sequence of the fragment. Such fragments can be chosen basedon the ability to retain one or more of the biological activities of thevariant protein or the ability to perform a function, e.g., act as animmunogen. Particularly important fragments are biologically activefragments. Such fragments will typically comprise a domain or motif of avariant protein of the present invention, e.g., active site,transmembrane domain, or ligand/substrate binding domain. Otherfragments include, but are not limited to, domain or motif-containingfragments, soluble peptide fragments, and fragments containingimmunogenic structures. Predicted domains and functional sites arereadily identifiable by computer programs well known to those of skillin the art (e.g., PROSITE analysis). Current Protocols in ProteinScience, John Wiley & Sons, N.Y. (2002).

Uses of Variant Proteins

The variant proteins of the present invention can be used in a varietyof ways, including but not limited to, in assays to determine thebiological activity of a variant protein, such as in a panel of multipleproteins for high-throughput screening; to raise antibodies or to elicitanother type of immune response; as a reagent (including the labeledreagent) in assays designed to quantitatively determine levels of thevariant protein (or its binding partner) in biological fluids; as amarker for cells or tissues in which it is preferentially expressed(either constitutively or at a particular stage of tissuedifferentiation or development or in a disease state); as a target forscreening for a therapeutic agent; and as a direct therapeutic agent tobe administered into a human subject. Any of the variant proteinsdisclosed herein may be developed into reagent grade or kit format forcommercialization as research products. Methods for performing the useslisted above are well known to those skilled in the art. See, e.g.,Molecular Cloning: A Laboratory Manual, Sambrook and Russell, ColdSpring Harbor Laboratory Press, N.Y. (2000), and Methods in Enzymology:Guide to Molecular Cloning Techniques, S. L. Berger and A. R. Kimmel,eds., Academic Press (1987).

In a specific embodiment of the invention, the methods of the presentinvention include detection of one or more variant proteins disclosedherein. Variant proteins are disclosed in Table 1 and in the SequenceListing as SEQ ID NOS:3-4. Detection of such proteins can beaccomplished using, for example, antibodies, small molecule compounds,aptamers, ligands/substrates, other proteins or protein fragments, orother protein-binding agents. Preferably, protein detection agents arespecific for a variant protein of the present invention and cantherefore discriminate between a variant protein of the presentinvention and the wild-type protein or another variant form. This cangenerally be accomplished by, for example, selecting or designingdetection agents that bind to the region of a protein that differsbetween the variant and wild-type protein, such as a region of a proteinthat contains one or more amino acid substitutions that is/are encodedby a non-synonymous cSNP of the present invention, or a region of aprotein that follows a nonsense mutation-type SNP that creates a stopcodon thereby leading to a shorter polypeptide, or a region of a proteinthat follows a read-through mutation-type SNP that destroys a stop codonthereby leading to a longer polypeptide in which a portion of thepolypeptide is present in one version of the polypeptide but not theother.

In another specific aspect of the invention, the variant proteins of thepresent invention are used as targets for diagnosing psoriasis or fordetermining predisposition to psoriasis in a human, for treating and/orpreventing psoriasis, or for predicting an individual's response to adrug treatment (particularly treatment or prevention of psoriasis), etc.Accordingly, the invention provides methods for detecting the presenceof, or levels of, one or more variant proteins of the present inventionin a cell, tissue, or organism. Such methods typically involvecontacting a test sample with an agent (e.g., an antibody, smallmolecule compound, or peptide) capable of interacting with the variantprotein such that specific binding of the agent to the variant proteincan be detected. Such an assay can be provided in a single detectionformat or a multi-detection format such as an array, for example, anantibody or aptamer array (arrays for protein detection may also bereferred to as “protein chips”). The variant protein of interest can beisolated from a test sample and assayed for the presence of a variantamino acid sequence encoded by one or more SNPs disclosed by the presentinvention. The SNPs may cause changes to the protein and thecorresponding protein function/activity, such as through non-synonymoussubstitutions in protein coding regions that can lead to amino acidsubstitutions, deletions, insertions, and/or rearrangements; formationor destruction of stop codons; or alteration of control elements such aspromoters. SNPs may also cause inappropriate post-translationalmodifications.

One preferred agent for detecting a variant protein in a sample is anantibody capable of selectively binding to a variant form of the protein(antibodies are described in greater detail in the next section). Suchsamples include, for example, tissues, cells, and biological fluidsisolated from a subject, as well as tissues, cells and fluids presentwithin a subject.

In vitro methods for detection of the variant proteins associated withpsoriasis that are disclosed herein and fragments thereof include, butare not limited to, enzyme linked immunosorbent assays (ELISAs),radioimmunoassays (RIA), Western blots, immunoprecipitations,immunofluorescence, and protein arrays/chips (e.g., arrays of antibodiesor aptamers). For further information regarding immunoassays and relatedprotein detection methods, see Current Protocols in Immunology, JohnWiley & Sons, N.Y., and Hage, “Immunoassays,” Anal Chem 15;71(12):294R-304R (June 1999).

Additional analytic methods of detecting amino acid variants include,but are not limited to, altered electrophoretic mobility, alteredtryptic peptide digest, altered protein activity in cell-based orcell-free assay, alteration in ligand or antibody-binding pattern,altered isoelectric point, and direct amino acid sequencing.

Alternatively, variant proteins can be detected in vivo in a subject byintroducing into the subject a labeled antibody (or other type ofdetection reagent) specific for a variant protein. For example, theantibody can be labeled with a radioactive marker whose presence andlocation in a subject can be detected by standard imaging techniques.

Other uses of the variant peptides of the present invention are based onthe class or action of the protein. For example, proteins isolated fromhumans and their mammalian orthologs serve as targets for identifyingagents (e.g., small molecule drugs or antibodies) for use in therapeuticapplications, particularly for modulating a biological or pathologicalresponse in a cell or tissue that expresses the protein. Pharmaceuticalagents can be developed that modulate protein activity.

As an alternative to modulating gene expression, therapeutic compoundscan be developed that modulate protein function. For example, many SNPsdisclosed herein affect the amino acid sequence of the encoded protein(e.g., non-synonymous cSNPs and nonsense mutation-type SNPs). Suchalterations in the encoded amino acid sequence may affect proteinfunction, particularly if such amino acid sequence variations occur infunctional protein domains, such as catalytic domains, ATP-bindingdomains, or ligand/substrate binding domains. It is well established inthe art that variant proteins having amino acid sequence variations infunctional domains can cause or influence pathological conditions. Insuch instances, compounds (e.g., small molecule drugs or antibodies) canbe developed that target the variant protein and modulate (e.g., up- ordown-regulate) protein function/activity.

The therapeutic methods of the present invention further include methodsthat target one or more variant proteins of the present invention.Variant proteins can be targeted using, for example, small moleculecompounds, antibodies, aptamers, ligands/substrates, other proteins, orother protein-binding agents. Additionally, the skilled artisan willrecognize that the novel protein variants (and polymorphic nucleic acidmolecules) disclosed in Table 1 may themselves be directly used astherapeutic agents by acting as competitive inhibitors of correspondingart-known proteins (or nucleic acid molecules such as mRNA molecules).

The variant proteins of the present invention are particularly useful indrug screening assays, in cell-based or cell-free systems. Cell-basedsystems can utilize cells that naturally express the protein, a biopsyspecimen, or cell cultures. In one embodiment, cell-based assays involverecombinant host cells expressing the variant protein. Cell-free assayscan be used to detect the ability of a compound to directly bind to avariant protein or to the corresponding SNP-containing nucleic acidfragment that encodes the variant protein.

A variant protein of the present invention, as well as appropriatefragments thereof, can be used in high-throughput screening assays totest candidate compounds for the ability to bind and/or modulate theactivity of the variant protein. These candidate compounds can befurther screened against a protein having normal function (e.g., awild-type/non-variant protein) to further determine the effect of thecompound on the protein activity. Furthermore, these compounds can betested in animal or invertebrate systems to determine in vivoactivity/effectiveness. Compounds can be identified that activate(agonists) or inactivate (antagonists) the variant protein, anddifferent compounds can be identified that cause various degrees ofactivation or inactivation of the variant protein.

Further, the variant proteins can be used to screen a compound for theability to stimulate or inhibit interaction between the variant proteinand a target molecule that normally interacts with the protein. Thetarget can be a ligand, a substrate or a binding partner that theprotein normally interacts with (for example, epinephrine ornorepinephrine). Such assays typically include the steps of combiningthe variant protein with a candidate compound under conditions thatallow the variant protein, or fragment thereof, to interact with thetarget molecule, and to detect the formation of a complex between theprotein and the target or to detect the biochemical consequence of theinteraction with the variant protein and the target, such as any of theassociated effects of signal transduction.

Candidate compounds include, for example, 1) peptides such as solublepeptides, including Ig-tailed fusion peptides and members of randompeptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991);Houghten et al., Nature 354:84-86 (1991)) and combinatorialchemistry-derived molecular libraries made of D- and/or L-configurationamino acids; 2) phosphopeptides (e.g., members of random and partiallydegenerate, directed phosphopeptide libraries, see, e.g., Songyang etal., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal,monoclonal, humanized, anti-idiotypic, chimeric, and single chainantibodies as well as Fab, F(ab′)₂, Fab expression library fragments,and epitope-binding fragments of antibodies); and 4) small organic andinorganic molecules (e.g., molecules obtained from combinatorial andnatural product libraries).

One candidate compound is a soluble fragment of the variant protein thatcompetes for ligand binding. Other candidate compounds include mutantproteins or appropriate fragments containing mutations that affectvariant protein function and thus compete for ligand. Accordingly, afragment that competes for ligand, for example with a higher affinity,or a fragment that binds ligand but does not allow release, isencompassed by the invention.

The invention further includes other end point assays to identifycompounds that modulate (stimulate or inhibit) variant protein activity.The assays typically involve an assay of events in the signaltransduction pathway that indicate protein activity. Thus, theexpression of genes that are up or down-regulated in response to thevariant protein dependent signal cascade can be assayed. In oneembodiment, the regulatory region of such genes can be operably linkedto a marker that is easily detectable, such as luciferase.Alternatively, phosphorylation of the variant protein, or a variantprotein target, could also be measured. Any of the biological orbiochemical functions mediated by the variant protein can be used as anendpoint assay. These include all of the biochemical or biologicalevents described herein, in the references cited herein, incorporated byreference for these endpoint assay targets, and other functions known tothose of ordinary skill in the art.

Binding and/or activating compounds can also be screened by usingchimeric variant proteins in which an amino terminal extracellulardomain or parts thereof, an entire transmembrane domain or subregions,and/or the carboxyl terminal intracellular domain or parts thereof, canbe replaced by heterologous domains or subregions. For example, asubstrate-binding region can be used that interacts with a differentsubstrate than that which is normally recognized by a variant protein.Accordingly, a different set of signal transduction components isavailable as an end-point assay for activation. This allows for assaysto be performed in other than the specific host cell from which thevariant protein is derived.

The variant proteins are also useful in competition binding assays inmethods designed to discover compounds that interact with the variantprotein. Thus, a compound can be exposed to a variant protein underconditions that allow the compound to bind or to otherwise interact withthe variant protein. A binding partner, such as ligand, that normallyinteracts with the variant protein is also added to the mixture. If thetest compound interacts with the variant protein or its binding partner,it decreases the amount of complex formed or activity from the variantprotein. This type of assay is particularly useful in screening forcompounds that interact with specific regions of the variant protein.Hodgson, Bio/technology, 10(9), 973-80 (September 1992).

To perform cell-free drug screening assays, it is sometimes desirable toimmobilize either the variant protein or a fragment thereof, or itstarget molecule, to facilitate separation of complexes from uncomplexedforms of one or both of the proteins, as well as to accommodateautomation of the assay. Any method for immobilizing proteins onmatrices can be used in drug screening assays. In one embodiment, afusion protein containing an added domain allows the protein to be boundto a matrix. For example, glutathione-S-transferase/¹²⁵I fusion proteinscan be adsorbed onto glutathione sepharose beads (Sigma Chemical, St.Louis, Mo.) or glutathione derivatized microtitre plates, which are thencombined with the cell lysates (e.g., ³⁵S-labeled) and a candidatecompound, such as a drug candidate, and the mixture incubated underconditions conducive to complex formation (e.g., at physiologicalconditions for salt and pH). Following incubation, the beads can bewashed to remove any unbound label, and the matrix immobilized andradiolabel determined directly, or in the supernatant after thecomplexes are dissociated. Alternatively, the complexes can bedissociated from the matrix, separated by SDS-PAGE, and the level ofbound material found in the bead fraction quantitated from the gel usingstandard electrophoretic techniques.

Either the variant protein or its target molecule can be immobilizedutilizing conjugation of biotin and streptavidin. Alternatively,antibodies reactive with the variant protein but which do not interferewith binding of the variant protein to its target molecule can bederivatized to the wells of the plate, and the variant protein trappedin the wells by antibody conjugation. Preparations of the targetmolecule and a candidate compound are incubated in the variantprotein-presenting wells and the amount of complex trapped in the wellcan be quantitated. Methods for detecting such complexes, in addition tothose described above for the GST-immobilized complexes, includeimmunodetection of complexes using antibodies reactive with the proteintarget molecule, or which are reactive with variant protein and competewith the target molecule, and enzyme-linked assays that rely ondetecting an enzymatic activity associated with the target molecule.

Modulators of variant protein activity identified according to thesedrug screening assays can be used to treat a subject with a disordermediated by the protein pathway, such as psoriasis. These methods oftreatment typically include the steps of administering the modulators ofprotein activity in a pharmaceutical composition to a subject in need ofsuch treatment.

The variant proteins, or fragments thereof, disclosed herein canthemselves be directly used to treat a disorder characterized by anabsence of, inappropriate, or unwanted expression or activity of thevariant protein. Accordingly, methods for treatment include the use of avariant protein disclosed herein or fragments thereof.

In yet another aspect of the invention, variant proteins can be used as“bait proteins” in a two-hybrid assay or three-hybrid assay to identifyother proteins that bind to or interact with the variant protein and areinvolved in variant protein activity. See, e.g., U.S. Pat. No.5,283,317; Zervos et al., Cell 72:223-232 (1993); Madura et al., J BiolChem 268:12046-12054 (1993); Bartel et al., Biotechniques 14:920-924(1993); Iwabuchi et al., Oncogene 8:1693-1696 (1993); and Brent, WO94/10300. Such variant protein-binding proteins are also likely to beinvolved in the propagation of signals by the variant proteins orvariant protein targets as, for example, elements of a protein-mediatedsignaling pathway. Alternatively, such variant protein-binding proteinsare inhibitors of the variant protein.

The two-hybrid system is based on the modular nature of mosttranscription factors, which typically consist of separable DNA-bindingand activation domains. Briefly, the assay typically utilizes twodifferent DNA constructs. In one construct, the gene that codes for avariant protein is fused to a gene encoding the DNA binding domain of aknown transcription factor (e.g., GAL-4). In the other construct, a DNAsequence, from a library of DNA sequences, that encodes an unidentifiedprotein (“prey” or “sample”) is fused to a gene that codes for theactivation domain of the known transcription factor. If the “bait” andthe “prey” proteins are able to interact, in vivo, forming a variantprotein-dependent complex, the DNA-binding and activation domains of thetranscription factor are brought into close proximity. This proximityallows transcription of a reporter gene (e.g., LacZ) that is operablylinked to a transcriptional regulatory site responsive to thetranscription factor. Expression of the reporter gene can be detected,and cell colonies containing the functional transcription factor can beisolated and used to obtain the cloned gene that encodes the proteinthat interacts with the variant protein.

Antibodies Directed to Variant Proteins

The present invention also provides antibodies that selectively bind tothe variant proteins disclosed herein and fragments thereof. Suchantibodies may be used to quantitatively or qualitatively detect thevariant proteins of the present invention. As used herein, an antibodyselectively binds a target variant protein when it binds the variantprotein and does not significantly bind to non-variant proteins, i.e.,the antibody does not significantly bind to normal, wild-type, orart-known proteins that do not contain a variant amino acid sequence dueto one or more SNPs of the present invention (variant amino acidsequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPsthat create a stop codon, thereby causing a truncation of a polypeptideor SNPs that cause read-through mutations resulting in an extension of apolypeptide).

As used herein, an antibody is defined in terms consistent with thatrecognized in the art: they are multi-subunit proteins produced by anorganism in response to an antigen challenge. The antibodies of thepresent invention include both monoclonal antibodies and polyclonalantibodies, as well as antigen-reactive proteolytic fragments of suchantibodies, such as Fab, F(ab)′₂, and Fv fragments. In addition, anantibody of the present invention further includes any of a variety ofengineered antigen-binding molecules such as a chimeric antibody (U.S.Pat. Nos. 4,816,567 and 4,816,397; Morrison et al., Proc Natl Acad SciUSA 81:6851 (1984); Neuberger et al., Nature 312:604 (1984)), ahumanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089 and 5,565,332),a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et al., Nature 334:544(1989)), a bispecific antibody with two binding specificities (Segal etal., J Immunol Methods 248:1 (2001); Carter, J Immunol Methods 248:7(2001)), a diabody, a triabody, and a tetrabody (Todorovska et al., JImmunol Methods 248:47 (2001)), as well as a Fab conjugate (dimer ortrimer), and a minibody.

Many methods are known in the art for generating and/or identifyingantibodies to a given target antigen. Harlow, Antibodies, Cold SpringHarbor Press, N.Y. (1989). In general, an isolated peptide (e.g., avariant protein of the present invention) is used as an immunogen and isadministered to a mammalian organism, such as a rat, rabbit, hamster ormouse. Either a full-length protein, an antigenic peptide fragment(e.g., a peptide fragment containing a region that varies between avariant protein and a corresponding wild-type protein), or a fusionprotein can be used. A protein used as an immunogen may benaturally-occurring, synthetic or recombinantly produced, and may beadministered in combination with an adjuvant, including but not limitedto, Freund's (complete and incomplete), mineral gels such as aluminumhydroxide, surface active substance such as lysolecithin, pluronicpolyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin,dinitrophenol, and the like.

Monoclonal antibodies can be produced by hybridoma technology, whichimmortalizes cells secreting a specific monoclonal antibody. Kohler andMilstein, Nature 256:495 (1975). The immortalized cell lines can becreated in vitro by fusing two different cell types, typicallylymphocytes, and tumor cells. The hybridoma cells may be cultivated invitro or in vivo. Additionally, fully human antibodies can be generatedby transgenic animals. He et al., J Immunol 169:595 (2002). Fd phage andFd phagemid technologies may be used to generate and select recombinantantibodies in vitro. Hoogenboom and Chames, Immunol Today 21:371 (2000);Liu et al., J Mol Biol 315:1063 (2002). The complementarity-determiningregions of an antibody can be identified, and synthetic peptidescorresponding to such regions may be used to mediate antigen binding.U.S. Pat. No. 5,637,677.

Antibodies are preferably prepared against regions or discrete fragmentsof a variant protein containing a variant amino acid sequence ascompared to the corresponding wild-type protein (e.g., a region of avariant protein that includes an amino acid encoded by a nonsynonymouscSNP, a region affected by truncation caused by a nonsense SNP thatcreates a stop codon, or a region resulting from the destruction of astop codon due to read-through mutation caused by a SNP). Furthermore,preferred regions will include those involved in function/activityand/or protein/binding partner interaction. Such fragments can beselected on a physical property, such as fragments corresponding toregions that are located on the surface of the protein, e.g.,hydrophilic regions, or can be selected based on sequence uniqueness, orbased on the position of the variant amino acid residue(s) encoded bythe SNPs provided by the present invention. An antigenic fragment willtypically comprise at least about 8-10 contiguous amino acid residues inwhich at least one of the amino acid residues is an amino acid affectedby a SNP disclosed herein. The antigenic peptide can comprise, however,at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) ormore amino acid residues, provided that at least one amino acid isaffected by a SNP disclosed herein.

Detection of an antibody of the present invention can be facilitated bycoupling (i.e., physically linking) the antibody or an antigen-reactivefragment thereof to a detectable substance. Detectable substancesinclude, but are not limited to, various enzymes, prosthetic groups,fluorescent materials, luminescent materials, bioluminescent materials,and radioactive materials. Examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, β-galactosidase, oracetylcholinesterase; examples of suitable prosthetic group complexesinclude streptavidin/biotin and avidin/biotin; examples of suitablefluorescent materials include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; an example of a luminescent material includesluminol; examples of bioluminescent materials include luciferase,luciferin, and aequorin, and examples of suitable radioactive materialinclude ¹²⁵I, ¹³¹I, ³⁵S or ³H.

Antibodies, particularly the use of antibodies as therapeutic agents,are reviewed in: Morgan, “Antibody therapy for Alzheimer's disease,”Expert Rev Vaccines (1):53-9 (February 2003); Ross et al., “Anticancerantibodies,” Am J Clin Pathol 119(4):472-85 (April 2003); Goldenberg,“Advancing role of radiolabeled antibodies in the therapy of cancer,”Cancer Immunol Immunother 52(5):281-96 (May

2003); Epub Mar. 11, 2003; Ross et al., “Antibody-based therapeutics inoncology,” Expert Rev Anticancer Ther 3(1):107-21 (February 2003); Caoet al., “Bispecific antibody conjugates in therapeutics,” Adv Drug DelivRev 55(2):171-97 (February 2003); von Mehren et al., “Monoclonalantibody therapy for cancer,” Annu Rev Med 54:343-69 (2003); Epub Dec.3, 2001; Hudson et al., “Engineered antibodies,” Nat Med 9(1):129-34(January 2003); Brekke et al., “Therapeutic antibodies for humandiseases at the dawn of the twenty-first century,” Nat Rev Drug Discov2(1):52-62 (January 2003); Erratum in: Nat Rev Drug Discov 2(3):240(March 2003); Houdebine, “Antibody manufacture in transgenic animals andcomparisons with other systems,” Curr Opin Biotechnol 13(6):625-9(December 2002); Andreakos et al., “Monoclonal antibodies in immune andinflammatory diseases,” Curr Opin Biotechnol 13(6):615-20 (December2002); Kellermann et al., “Antibody discovery: the use of transgenicmice to generate human monoclonal antibodies for therapeutics,” CurrOpin Biotechnol 13(6):593-7 (December 2002); Pini et al., “Phage displayand colony filter screening for high-throughput selection of antibodylibraries,” Comb Chem High Throughput Screen 5(7):503-10 (November2002); Batra et al., “Pharmacokinetics and biodistribution ofgenetically engineered antibodies,” Curr Opin Biotechnol 13(6):603-8(December 2002); and Tangri et al., “Rationally engineered proteins orantibodies with absent or reduced immunogenicity,” Curr Med Chem9(24):2191-9 (December 2002).

Uses of Antibodies

Antibodies can be used to isolate the variant proteins of the presentinvention from a natural cell source or from recombinant host cells bystandard techniques, such as affinity chromatography orimmunoprecipitation. In addition, antibodies are useful for detectingthe presence of a variant protein of the present invention in cells ortissues to determine the pattern of expression of the variant proteinamong various tissues in an organism and over the course of normaldevelopment or disease progression. Further, antibodies can be used todetect variant protein in situ, in vitro, in a bodily fluid, or in acell lysate or supernatant in order to evaluate the amount and patternof expression. Also, antibodies can be used to assess abnormal tissuedistribution, abnormal expression during development, or expression inan abnormal condition, such as in psoriasis, or during drug treatment.Additionally, antibody detection of circulating fragments of thefull-length variant protein can be used to identify turnover.

Antibodies to the variant proteins of the present invention are alsouseful in pharmacogenomic analysis. Thus, antibodies against variantproteins encoded by alternative SNP alleles can be used to identifyindividuals that require modified treatment modalities.

Further, antibodies can be used to assess expression of the variantprotein in disease states such as in active stages of the disease or inan individual with a predisposition to a disease related to theprotein's function, such as psoriasis, or during the course of atreatment regime. Antibodies specific for a variant protein encoded by aSNP-containing nucleic acid molecule of the present invention can beused to assay for the presence of the variant protein, such as todiagnose psoriasis or to predict an individual's response to a drugtreatment or predisposition/susceptibility to psoriasis, as indicated bythe presence of the variant protein.

Antibodies are also useful as diagnostic tools for evaluating thevariant proteins in conjunction with analysis by electrophoreticmobility, isoelectric point, tryptic peptide digest, and other physicalassays well known in the art.

Antibodies are also useful for tissue typing. Thus, where a specificvariant protein has been correlated with expression in a specifictissue, antibodies that are specific for this protein can be used toidentify a tissue type.

Antibodies can also be used to assess aberrant subcellular localizationof a variant protein in cells in various tissues. The diagnostic usescan be applied, not only in genetic testing, but also in monitoring atreatment modality. Accordingly, where treatment is ultimately aimed atcorrecting the expression level or the presence of variant protein oraberrant tissue distribution or developmental expression of a variantprotein, antibodies directed against the variant protein or relevantfragments can be used to monitor therapeutic efficacy.

The antibodies are also useful for inhibiting variant protein function,for example, by blocking the binding of a variant protein to a bindingpartner. These uses can also be applied in a therapeutic context inwhich treatment involves inhibiting a variant protein's function. Anantibody can be used, for example, to block or competitively inhibitbinding, thus modulating (agonizing or antagonizing) the activity of avariant protein. Antibodies can be prepared against specific variantprotein fragments containing sites required for function or against anintact variant protein that is associated with a cell or cell membrane.For in vivo administration, an antibody may be linked with an additionaltherapeutic payload such as a radionuclide, an enzyme, an immunogenicepitope, or a cytotoxic agent. Suitable cytotoxic agents include, butare not limited to, bacterial toxin such as diphtheria, and plant toxinsuch as ricin. The in vivo half-life of an antibody or a fragmentthereof may be lengthened by pegylation through conjugation topolyethylene glycol. Leong et al., Cytokine 16:106 (2001).

The invention also encompasses kits for using antibodies, such as kitsfor detecting the presence of a variant protein in a test sample. Anexemplary kit can comprise antibodies such as a labeled or labelableantibody and a compound or agent for detecting variant proteins in abiological sample; means for determining the amount, or presence/absenceof variant protein in the sample; means for comparing the amount ofvariant protein in the sample with a standard; and instructions for use.

Vectors and Host Cells

The present invention also provides vectors containing theSNP-containing nucleic acid molecules described herein. The term“vector” refers to a vehicle, preferably a nucleic acid molecule, whichcan transport a SNP-containing nucleic acid molecule. When the vector isa nucleic acid molecule, the SNP-containing nucleic acid molecule can becovalently linked to the vector nucleic acid. Such vectors include, butare not limited to, a plasmid, single or double stranded phage, a singleor double stranded RNA or DNA viral vector, or artificial chromosome,such as a BAC, PAC, YAC, or MAC.

A vector can be maintained in a host cell as an extrachromosomal elementwhere it replicates and produces additional copies of the SNP-containingnucleic acid molecules. Alternatively, the vector may integrate into thehost cell genome and produce additional copies of the SNP-containingnucleic acid molecules when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) orvectors for expression (expression vectors) of the SNP-containingnucleic acid molecules. The vectors can function in prokaryotic oreukaryotic cells or in both (shuttle vectors).

Expression vectors typically contain cis-acting regulatory regions thatare operably linked in the vector to the SNP-containing nucleic acidmolecules such that transcription of the SNP-containing nucleic acidmolecules is allowed in a host cell. The SNP-containing nucleic acidmolecules can also be introduced into the host cell with a separatenucleic acid molecule capable of affecting transcription. Thus, thesecond nucleic acid molecule may provide a trans-acting factorinteracting with the cis-regulatory control region to allowtranscription of the SNP-containing nucleic acid molecules from thevector. Alternatively, a trans-acting factor may be supplied by the hostcell. Finally, a trans-acting factor can be produced from the vectoritself. It is understood, however, that in some embodiments,transcription and/or translation of the nucleic acid molecules can occurin a cell-free system.

The regulatory sequences to which the SNP-containing nucleic acidmolecules described herein can be operably linked include promoters fordirecting mRNA transcription. These include, but are not limited to, theleft promoter from bacteriophage λ, the lac, TRP, and TAC promoters fromE. coli, the early and late promoters from SV40, the CMV immediate earlypromoter, the adenovirus early and late promoters, and retroviruslong-terminal repeats.

In addition to control regions that promote transcription, expressionvectors may also include regions that modulate transcription, such asrepressor binding sites and enhancers. Examples include the SV40enhancer, the cytomegalovirus immediate early enhancer, polyomaenhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation andcontrol, expression vectors can also contain sequences necessary fortranscription termination and, in the transcribed region, aribosome-binding site for translation. Other regulatory control elementsfor expression include initiation and termination codons as well aspolyadenylation signals. A person of ordinary skill in the art would beaware of the numerous regulatory sequences that are useful in expressionvectors. See, e.g., Sambrook and Russell, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

A variety of expression vectors can be used to express a SNP-containingnucleic acid molecule. Such vectors include chromosomal, episomal, andvirus-derived vectors, for example, vectors derived from bacterialplasmids, from bacteriophage, from yeast episomes, from yeastchromosomal elements, including yeast artificial chromosomes, fromviruses such as baculoviruses, papovaviruses such as SV40, Vacciniaviruses, adenoviruses, poxviruses, pseudorabies viruses, andretroviruses. Vectors can also be derived from combinations of thesesources such as those derived from plasmid and bacteriophage geneticelements, e.g., cosmids and phagemids. Appropriate cloning andexpression vectors for prokaryotic and eukaryotic hosts are described inSambrook and Russell, Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, N.Y. (2000).

The regulatory sequence in a vector may provide constitutive expressionin one or more host cells (e.g., tissue specific expression) or mayprovide for inducible expression in one or more cell types such as bytemperature, nutrient additive, or exogenous factor, e.g., a hormone orother ligand. A variety of vectors that provide constitutive orinducible expression of a nucleic acid sequence in prokaryotic andeukaryotic host cells are well known to those of ordinary skill in theart.

A SNP-containing nucleic acid molecule can be inserted into the vectorby methodology well-known in the art. Generally, the SNP-containingnucleic acid molecule that will ultimately be expressed is joined to anexpression vector by cleaving the SNP-containing nucleic acid moleculeand the expression vector with one or more restriction enzymes and thenligating the fragments together. Procedures for restriction enzymedigestion and ligation are well known to those of ordinary skill in theart.

The vector containing the appropriate nucleic acid molecule can beintroduced into an appropriate host cell for propagation or expressionusing well-known techniques. Bacterial host cells include, but are notlimited to, Escherichia coli, Streptomyces spp., and Salmonellatyphimurium. Eukaryotic host cells include, but are not limited to,yeast, insect cells such as Drosophila spp., animal cells such as COSand CHO cells, and plant cells.

As described herein, it may be desirable to express the variant peptideas a fusion protein. Accordingly, the invention provides fusion vectorsthat allow for the production of the variant peptides. Fusion vectorscan, for example, increase the expression of a recombinant protein,increase the solubility of the recombinant protein, and aid in thepurification of the protein by acting, for example, as a ligand foraffinity purification. A proteolytic cleavage site may be introduced atthe junction of the fusion moiety so that the desired variant peptidecan ultimately be separated from the fusion moiety. Proteolytic enzymessuitable for such use include, but are not limited to, factor Xa,thrombin, and enterokinase. Typical fusion expression vectors includepGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs,Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuseglutathione S-transferase (GST), maltose E binding protein, or proteinA, respectively, to the target recombinant protein. Examples of suitableinducible non-fusion E. coli expression vectors include pTrc (Amann etal., Gene 69:301-315 (1988)) and pET 11d (Studier et al., GeneExpression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a bacterial host byproviding a genetic background wherein the host cell has an impairedcapacity to proteolytically cleave the recombinant protein (S.Gottesman, Gene Expression Technology: Methods in Enzymology185:119-128, Academic Press, Calif. (1990)). Alternatively, the sequenceof the SNP-containing nucleic acid molecule of interest can be alteredto provide preferential codon usage for a specific host cell, forexample, E. coli. Wada et al., Nucleic Acids Res 20:2111-2118 (1992).

The SNP-containing nucleic acid molecules can also be expressed byexpression vectors that are operative in yeast. Examples of vectors forexpression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari etal., EMBO J 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943(1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2(Invitrogen Corporation, San Diego, Calif.).

The SNP-containing nucleic acid molecules can also be expressed ininsect cells using, for example, baculovirus expression vectors.Baculovirus vectors available for expression of proteins in culturedinsect cells (e.g., Sf 9 cells) include the pAc series (Smith et al.,Mol Cell Biol 3:2156-2165 (1983)) and the pVL series (Lucklow et al.,Virology 170:31-39 (1989)).

In certain embodiments of the invention, the SNP-containing nucleic acidmolecules described herein are expressed in mammalian cells usingmammalian expression vectors. Examples of mammalian expression vectorsinclude pCDM8 (B. Seed, Nature 329:840 (1987)) and pMT2PC (Kaufman etal., EMBO J 6:187-195 (1987)).

The invention also encompasses vectors in which the SNP-containingnucleic acid molecules described herein are cloned into the vector inreverse orientation, but operably linked to a regulatory sequence thatpermits transcription of antisense RNA. Thus, an antisense transcriptcan be produced to the SNP-containing nucleic acid sequences describedherein, including both coding and non-coding regions. Expression of thisantisense RNA is subject to each of the parameters described above inrelation to expression of the sense RNA (regulatory sequences,constitutive or inducible expression, tissue-specific expression).

The invention also relates to recombinant host cells containing thevectors described herein. Host cells therefore include, for example,prokaryotic cells, lower eukaryotic cells such as yeast, othereukaryotic cells such as insect cells, and higher eukaryotic cells suchas mammalian cells.

The recombinant host cells can be prepared by introducing the vectorconstructs described herein into the cells by techniques readilyavailable to persons of ordinary skill in the art. These include, butare not limited to, calcium phosphate transfection,DEAE-dextran-mediated transfection, cationic lipid-mediatedtransfection, electroporation, transduction, infection, lipofection, andother techniques such as those described in Sambrook and Russell,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Press, N.Y. (2000).

Host cells can contain more than one vector. Thus, differentSNP-containing nucleotide sequences can be introduced in differentvectors into the same cell. Similarly, the SNP-containing nucleic acidmolecules can be introduced either alone or with other nucleic acidmolecules that are not related to the SNP-containing nucleic acidmolecules, such as those providing trans-acting factors for expressionvectors. When more than one vector is introduced into a cell, thevectors can be introduced independently, co-introduced, or joined to thenucleic acid molecule vector.

In the case of bacteriophage and viral vectors, these can be introducedinto cells as packaged or encapsulated virus by standard procedures forinfection and transduction. Viral vectors can be replication-competentor replication-defective. In the case in which viral replication isdefective, replication can occur in host cells that provide functionsthat complement the defects.

Vectors generally include selectable markers that enable the selectionof the subpopulation of cells that contain the recombinant vectorconstructs. The marker can be inserted in the same vector that containsthe SNP-containing nucleic acid molecules described herein or may be ina separate vector. Markers include, for example, tetracycline orampicillin-resistance genes for prokaryotic host cells, anddihydrofolate reductase or neomycin resistance genes for eukaryotic hostcells. However, any marker that provides selection for a phenotypictrait can be effective.

While the mature variant proteins can be produced in bacteria, yeast,mammalian cells, and other cells under the control of the appropriateregulatory sequences, cell-free transcription and translation systemscan also be used to produce these variant proteins using RNA derivedfrom the DNA constructs described herein.

Where secretion of the variant protein is desired, which is difficult toachieve with multi-transmembrane domain containing proteins such asG-protein-coupled receptors (GPCRs), appropriate secretion signals canbe incorporated into the vector. The signal sequence can be endogenousto the peptides or heterologous to these peptides.

Where the variant protein is not secreted into the medium, the proteincan be isolated from the host cell by standard disruption procedures,including freeze/thaw, sonication, mechanical disruption, use of lysingagents, and the like. The variant protein can then be recovered andpurified by well-known purification methods including, for example,ammonium sulfate precipitation, acid extraction, anion or cationicexchange chromatography, phosphocellulose chromatography,hydrophobic-interaction chromatography, affinity chromatography,hydroxylapatite chromatography, lectin chromatography, or highperformance liquid chromatography.

It is also understood that, depending upon the host cell in whichrecombinant production of the variant proteins described herein occurs,they can have various glycosylation patterns, or may benon-glycosylated, as when produced in bacteria. In addition, the variantproteins may include an initial modified methionine in some cases as aresult of a host-mediated process.

For further information regarding vectors and host cells, see CurrentProtocols in Molecular Biology, John Wiley & Sons, N.Y.

Uses of Vectors and Host Cells, and Transgenic Animals

Recombinant host cells that express the variant proteins describedherein have a variety of uses. For example, the cells are useful forproducing a variant protein that can be further purified into apreparation of desired amounts of the variant protein or fragmentsthereof. Thus, host cells containing expression vectors are useful forvariant protein production.

Host cells are also useful for conducting cell-based assays involvingthe variant protein or variant protein fragments, such as thosedescribed above as well as other formats known in the art. Thus, arecombinant host cell expressing a variant protein is useful forassaying compounds that stimulate or inhibit variant protein function.Such an ability of a compound to modulate variant protein function maynot be apparent from assays of the compound on the native/wild-typeprotein, or from cell-free assays of the compound. Recombinant hostcells are also useful for assaying functional alterations in the variantproteins as compared with a known function.

Genetically-engineered host cells can be further used to producenon-human transgenic animals. A transgenic animal is preferably anon-human mammal, for example, a rodent, such as a rat or mouse, inwhich one or more of the cells of the animal include a transgene. Atransgene is exogenous DNA containing a SNP of the present inventionwhich is integrated into the genome of a cell from which a transgenicanimal develops and which remains in the genome of the mature animal inone or more of its cell types or tissues. Such animals are useful forstudying the function of a variant protein in vivo, and identifying andevaluating modulators of variant protein activity. Other examples oftransgenic animals include, but are not limited to, non-human primates,sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-humanmammals such as cows and goats can be used to produce variant proteinswhich can be secreted in the animal's milk and then recovered.

A transgenic animal can be produced by introducing a SNP-containingnucleic acid molecule into the male pronuclei of a fertilized oocyte,e.g., by microinjection or retroviral infection, and allowing the oocyteto develop in a pseudopregnant female foster animal. Any nucleic acidmolecules that contain one or more SNPs of the present invention canpotentially be introduced as a transgene into the genome of a non-humananimal.

Any of the regulatory or other sequences useful in expression vectorscan form part of the transgenic sequence. This includes intronicsequences and polyadenylation signals, if not already included. Atissue-specific regulatory sequence(s) can be operably linked to thetransgene to direct expression of the variant protein in particularcells or tissues.

Methods for generating transgenic animals via embryo manipulation andmicroinjection, particularly animals such as mice, have becomeconventional in the art and are described, for example, in U.S. Pat.Nos. 4,736,866 and 4,870,009, both by Leder et al.; U.S. Pat. No.4,873,191 by Wagner et al., and in B. Hogan, Manipulating the MouseEmbryo, Cold Spring Harbor Laboratory Press, N.Y. (1986). Similarmethods are used for production of other transgenic animals. Atransgenic founder animal can be identified based upon the presence ofthe transgene in its genome and/or expression of transgenic mRNA intissues or cells of the animals. A transgenic founder animal can then beused to breed additional animals carrying the transgene. Moreover,transgenic animals carrying a transgene can further be bred to othertransgenic animals carrying other transgenes. A transgenic animal alsoincludes a non-human animal in which the entire animal or tissues in theanimal have been produced using the homologously recombinant host cellsdescribed herein.

In another embodiment, transgenic non-human animals can be producedwhich contain selected systems that allow for regulated expression ofthe transgene. One example of such a system is the cre/loxP recombinasesystem of bacteriophage P1. Lakso et al., PNAS 89:6232-6236 (1992).Another example of a recombinase system is the FLP recombinase system ofS. cerevisiae. O'Gorman et al., Science 251:1351-1355 (1991). If acre/loxP recombinase system is used to regulate expression of thetransgene, animals containing transgenes encoding both the Crerecombinase and a selected protein are generally needed. Such animalscan be provided through the construction of “double” transgenic animals,e.g., by mating two transgenic animals, one containing a transgeneencoding a selected variant protein and the other containing a transgeneencoding a recombinase.

Clones of the non-human transgenic animals described herein can also beproduced according to the methods described, for example, in I. Wilmutet al., Nature 385:810-813 (1997) and PCT International Publication Nos.WO 97/07668 and WO 97/07669. In brief, a cell (e.g., a somatic cell)from the transgenic animal can be isolated and induced to exit thegrowth cycle and enter G_(o) phase. The quiescent cell can then befused, e.g., through the use of electrical pulses, to an enucleatedoocyte from an animal of the same species from which the quiescent cellis isolated. The reconstructed oocyte is then cultured such that itdevelops to morula or blastocyst and then transferred to pseudopregnantfemale foster animal. The offspring born of this female foster animalwill be a clone of the animal from which the cell (e.g., a somatic cell)is isolated.

Transgenic animals containing recombinant cells that express the variantproteins described herein are useful for conducting the assays describedherein in an in vivo context. Accordingly, the various physiologicalfactors that are present in vivo and that could influence ligand orsubstrate binding, variant protein activation, signal transduction, orother processes or interactions, may not be evident from in vitrocell-free or cell-based assays. Thus, non-human transgenic animals ofthe present invention may be used to assay in vivo variant proteinfunction as well as the activities of a therapeutic agent or compoundthat modulates variant protein function/activity or expression. Suchanimals are also suitable for assessing the effects of null mutations(i.e., mutations that substantially or completely eliminate one or morevariant protein functions).

For further information regarding transgenic animals, see Houdebine,“Antibody manufacture in transgenic animals and comparisons with othersystems,” Curr Opin Biotechnol 13(6):625-9 (December 2002); Petters etal., “Transgenic animals as models for human disease,” Transgenic Res9(4-5):347-51, discussion 345-6 (2000); Wolf et al., “Use of transgenicanimals in understanding molecular mechanisms of toxicity,” J PharmPharmacol 50(6):567-74 (June 1998); Echelard, “Recombinant proteinproduction in transgenic animals,” Curr Opin Biotechnol 7(5):536-40(October 1996); Houdebine, “Transgenic animal bioreactors,” TransgenicRes 9(4-5):305-20 (2000); Pirity et al., “Embryonic stem cells, creatingtransgenic animals,” Methods Cell Biol 57:279-93 (1998); and Robl etal., “Artificial chromosome vectors and expression of complex proteinsin transgenic animals,” Theriogenology 59(1):107-13 (January 2003).

EXAMPLES

The following examples are offered to illustrate, but not limit, theclaimed invention.

Example 1 Identification and Analysis of Haplotypes in the IL23R RegionAssociated with Psoriasis

Overview

To analyze the association of IL23R with psoriasis, a fine mappingstrategy was used to identify 59 additional IL23R-linked SNPs which weregenotyped in three independent, white North American sample sets (>2800individuals in toto). A sliding window of haplotype associationdemonstrates co-localization of psoriasis susceptibility effects withinthe boundaries of IL23R across all sample sets, thereby decreasing thelikelihood that neighboring genes, particularly IL12RB2, are driving theassociation at this region. Additional haplotype work identified two5-SNP haplotypes with strong protective effects, consistent across thethree sample sets (OR_(common)=0.67; P_(comb)=4.32E-07). Importantly,heterogeneity of effect was extremely low between sample sets for thesehaplotypes (P_(Het)=0.961). Together, these protective haplotypes attaina frequency of 16% in controls, declining to 11% in cases. Thecharacterization of association patterns within IL23R to specificpredisposing/protective variants enables uses of IL23R variants fordetermining an individual's risk for developing psoriasis (as well asrelated pathologies such as Crohn's disease) and for predicting anindividual's response to various pharmaceutical therapies and dosages,as well as other uses.

Results

Genotyping for this study was performed on three independent sample setsconsisting of white North American psoriasis cases and controls,totaling 1444 cases and 1382 controls. Basic demographic and clinicalcharacteristics of these sample sets are described in a previouspublication.² A type of genomic-control analysis was performed on pooledgenotype data from the initial sample set which effectively ruled outlarge population stratification effects.²

Applying a fine mapping SNP selection algorithm (described in the“Materials and Methods” section of Example 1 below), 59 additional SNPswere identified for interrogation in the three sample sets, for a totalof 61 SNPs covering 338 kb (rs7530511, P310L; and rs11209026, R381Q werepreviously genotyped in all three sample sets). 31 of these fine mappingSNPs were within the coding region or the 3′UTR of IL23R.

Of the 61 SNPs evaluated, eight had Mantel-Haenszel continuity-correctedP-values (MH P-values combine association evidence across the threesamples sets, accounting for direction of effect) below 0.05 (data notshown). Allele frequencies, genotypic 2-df P-values and P-values for theexact test of Hardy-Weinberg equilibrium for each sample set were alsodetermined for these SNPs, as well as Mantel-Haenszel allelic odds ratioand 95% confidence intervals (which were calculated jointly across thethree sample sets) (data not shown). Six of these eight significant SNPsreside within the IL23R coding region and the remaining two are locatedin the intergenic region between IL23R and IL12RB2. These eight SNPsinclude two previously reported missense SNPs, rs7530511 (P310L) andrs11209026 (R381Q).

Prior to tests of haplotype association, two types of graphicalrepresentations of linkage disequilibrium patterns were constructed: Tocharacterize the pairwise correlation structure for the entire 338 kbregion, a heatmap for cases and controls combined using the r² and D′statistics was generated (not shown). Individual pairwise LD values withcorresponding SNPs were calculated (data not shown). All three samplesets were combined for this analysis. The r² heatmap showed an absenceof solid block patterns. Rather, there are two very roughly-definedblock structures in the region with slightly higher average r² valuesthan the surrounding regions. These weak blocks are highly peppered withpairwise comparisons of low LD. More pronounced LD structure isdisplayed in the D′ heatmap, with two or three blocks covering theregion. Given the fine mapping SNP selection procedure employed whereSNPs were genotyped if they exhibited high LD (as measured by r²) withone of the originally associated missense SNPs (P310L or R381Q) andother SNPs were tagging SNPs reducing redundancy, the observance ofstrong block structures was unexpected. From the r² data, the first weakblock extends roughly from intron 3 of Clorf141 into the 5′ region ofIL12RB2 and the second weak block covers part of the first intron ofIL12RB2 through 28 kb 5′ of SERBP1.

Because much of the association signal was driven by rs11209026 (R381Q)and other studies have identified this missense polymorphism as beingstrongly associated with the related phenotypes studied, theMantel-Haenzsel P-value (combining the three sample sets) was plotted asa function of r² with R381Q (not shown). Under a model where R381Q issolely and causally responsible for the association patterns observed,one would expect the approximate relationship: log P_(M)≈r² log P_(D);where P_(M) is the association P-value at a marker in linkagedisequilibrium with the causative site, P_(D) is the association P-valueat the causative site, in this case R381Q, r² is the pairwise LD measurebetween the two sites and equal numbers of genotypes are assayed at eachsite. This association decay analysis suggests that some SNPs in low LDwith R381Q may independently contribute to disease status as theysubstantially depart from the expected relationship.

In a previous publication, haplotypes for P310L and R381Q wereconstructed since haplotype association tests can be more informativethan single marker test under many models where cis-effects play animportant role.³⁴ Even though these SNPs were not in high LD, the numberof double heterozygotes was small and hence linkage phase is unambiguousin the large majority of individuals. With these two missensepolymorphisms, carrying the proline-arginine polypeptide-encoding geneshows susceptible effects whereas both the leucine-arginine andproline-glutamine polypeptides confer protective effects. For thisstudy, the fine mapping data was used to scan this region positionallyfor haplotype effects using a sliding window approach. A window size ofthree adjacent SNPs was used. A positional plot of the global haplotypeP-value for each window was generated (not shown). The plot showed ananalysis combined across sample sets using the Fisher's combined P-valuemethod. The results indicated rather narrow peaks of associationcentering on IL23R intron 8 through intron 9 and including the R381Qpolymorphism in exon 9—a span of 12 kb. Four SNPs generated thisassociation signal: rs10789229, rs10889671, rs11209026 (R381Q), andrs10889674; with the first window (rs10789229-rs10889671-rs11209026)producing a combined global P-value (2-tailed in each sample set) of1.28E-04 and the second window (rs10889671-rs11209026-rs10889674)producing a combined global P-value (also 2-tailed in each sample set)of 6.42E-05. Through the association and LD analyses, it was apparentthat although these four IL23R SNPs generated the peak associationsignal, additional psoriasis-association effects may be possible throughhaplotypes derived from additional SNPs (e.g., P310L). Analysis ofpairwise LD and association results indicates that within the eight SNPshaving significant Mantel-Haenszel P-values, rs7530511 is highlycorrelated with rs10889671 (intron 8, IL23R SNP; r²=0.943); andsimilarly, rs11209026 is highly correlated with rs11465804 (intron 8,IL23R SNP; r²=0.852). These data were then interrogated with severalsubsequent haplotype analyses.

Another haplotype-based investigation was commenced by using the fiveSNPs that exhibited the strongest and most consistent single-SNPassociation signals: rs7530511, rs11465804, rs10889671, rs11209026 andrs1857292. These SNPs span 53 kb from exon 7 in IL23R to the intergenicregion between IL23R and IL12RB2. The five-SNP haplotypes were estimatedand tested for association in the three sample sets. Five primaryhaplotypes were found (above 1% frequency), two of which conferredsignificant protection against psoriasis susceptibility (Table 5).Together, these two (completely divergent) protective haplotypes, TTAGTand CGGAA, were present on 16% of control chromosomes, decreasing to 11%in cases. The effect of these protective haplotypes was consistentacross sample sets (OR_(SS1)=0.66, OR_(SS2)=0.67, OR_(SS3)=0.69), andthe combined analysis was rather significant (P_(MH)=4.32E-07).Importantly, the level of heterogeneity of effect was not significantacross sample sets for the protective haplotype grouping of TTAGT andCGGAA versus all other haplotypes (P_(Het)=0.961) as determined from theMantel-Haenszel procedure to test odds ratios for homogeneity (see the“Materials and Methods” section of Example 1 below).

All possible combinations of these five SNPs were then systematicallyevaluated in an exploratory analysis to see if one or more of these SNPscould be eliminated while retaining or increasing the significance ofthe association result. Eliminating rs11465804 and rs1857292 from thehaplotypes yielded a simpler, slightly stronger association result forthe protective haplotypes (TAG and CGA vs. Others; P_(MH)=3.88E-08)(Table 6) (although stochastic effects may not be ruled out). Withoutthese two SNPs, the frequencies of the resulting protective haplotypesincreased to 20% in controls and 14% in cases.

To better understand the physical extent of the protective haplotypes inthis region, the haplotype analysis was expanded to include allcontiguous markers such that the association signal was notsubstantially diminished by estimated historical recombination events.This region appeared to extend 55 kb from P310L through the 3′ region ofIL23R to rs11209032 in the IL23R-IL12RB2 intergenic region. Haplotypeanalysis was performed on all twenty-three markers in this region (Table7). Again, two common protective haplotypes were identified. Althoughthe initial five- and three-marker protective haplotypes described abovedid not share alleles at any sites, the two protective haplotypes fromthe twenty-three marker analysis had twelve markers with the samealleles on both haplotypes. As no other common (>1%) haplotypes sharedthe alleles at these twelve markers, the analysis was reduced to thosetwelve markers and another haplotype analysis was carried out (Table 8).Notably, the protective haplotype from this reduced set of SNPs,AGTTCCTCCCAG, carries substantial effects (freq in cases=12%, freq incontrols=17%; OR_(MH)=0.68; P_(MH)=3.18E-07) and does not include P310L,R381Q or SNPs in high LD with these two missense SNPs (rs10889671,rs1857292, or rs11465804). In addition, this haplotype is remarkablysimilar in frequency and effect size across all three sample sets (inthe case for the three marker haplotype rs7530511-rs10889671-rs11209026described previously, the TAG haplotype exhibited the strongestprotective effects in the Utah population-derived Sample Set 1 while theCGA haplotype was stronger in the remaining two sample sets which werederived from the North American white population in general).

To determine whether or not this 12-marker haplotype represents avariant contributing to psoriasis association independently of P310L andR381Q, the 12-marker haplotypes were dichotomized into the protectivehaplotype described above and an aggregate of all other haplotypes, andthen the same was done for the rs7530511-rs11209026 haplotypes (TG andCA protective haplotypes combined together vs. CG and TA combinedtogether). A diplotype-based, squared correlation coefficient r²statistic was then calculated between the two haplotype groupings. Allindividuals were used across all sample sets for this calculation. Theresulting value, r²=0.78, indicated a fairly high degree of correlationbetween the two diplotype groupings, thereby suggesting that althoughthey were not completely redundant, these were not independent effects.

The LD patterns and haplotype results appear to indicate that more thanone polymorphism is contributing to the psoriasis association linked toIL23R. To formally investigate this, a test of conditional associationwas performed on SNPs having the most significant combined P-values(P<0.005) for the 2df genotype test and exhibiting significantMantel-Haenzsel confidence intervals (95% CI excluding 1.0) for theallelic OR jointly calculated over the three sample sets. As some ofthese SNPs clustered into “LD groups” consisting of SNPs in very high LDand similar statistical significance for psoriasis association, arepresentative SNP was selected from each LD group when appropriate. SixSNPs met these criteria: the missense SNPs rs7520511 (P310L) andrs11209026 (R381Q), rs10889674 (putative transcription factor bindingsite, intron 9 IL23R), rs1857292 (3′ of IL23R), rs11465804 (intron 8 ofIL23R) and rs10889671 (intron 8 IL23R). Rs11465804 and rs10889671 wereexcluded from this analysis due to high LD with one of the missense SNPs(rs10889671-rs7530511 r²=0.943; rs11465804-rs11209026 r²=0.852) andsince both missense SNPs had slightly elevated significance whencompared to these LD counterparts. The conditional associationpermutation test revealed that the genotype association at R381Qremained significant after fixing the genotypes at P310L(P_(comb)=0.00031), or either of the remaining two SNPs(P_(comb)=0.0183, fixing genotypes at rs10889674; P_(comb)=0.0027,fixing genotypes at rs1857292). Conversely, the genotype association atP310L was also significant, albeit mildly so, following conditioning onR381Q genotypes (P_(comb)=0.0299); however the moderate LD between P310Land the other two SNPs removed the association at P310L. These resultsfor the mutually conditionally independent association of the twomissense SNPs were not unexpected given the very low amount of LDbetween these two SNPs. Hence, there is some evidence of at least twoIL23R-linked polymorphisms independently contributing to psoriasis.

As other SNPs, not genotyped in this study, could possibly drive theassociation results observed here, the HapMap LD results wereinvestigated for the CEU samples between genomic positions67,225,114-67,725,113 on Build36.³⁵ Examining four key SNPs from thisstudy, rs7530511, rs10889671, rs11465804, and rs11209026, seven SNPswere found to be in substantial LD (r²>0.50) with either rs7530511,rs10889671 or both: rs2863212 (IL23R intron 6), rs7528924 (IL23R intron7), rs4655692 (IL23R intron 7), rs4655693 (IL23R intron 7), rs11804284(IL23R intron 7), rs4655530 (IL23R intron 8), and rs2863209 (intragenic,within 8 kb 3′ of IL23R). The remaining two SNPs were only insubstantial LD with each other (r² _(rs11465804-rs11209026)=0.852).

Discussion

Fine mapping of the IL23R-linked region shows variants segregating atIL23R coding and flanking regions significantly associated withpsoriasis. In particular, there are extended haplotypes in this regionthat protect against psoriasis susceptibility. Importantly, it alsoappears that at least two IL23R polymorphisms, P310L and R381Q,independently contribute to linkage disequilibrium with the psoriasisphenotype. In addition, both sliding window haplotype analyses andlonger-range haplotype work pinpointed the association signal to theIL23R coding region. This is particularly important as the interleukin12 receptor subunit-encoding gene, IL12RB2, is located 47 kb from the 3′end of IL23R and some SNP pairs exhibit substantial and even perfectlinkage disequilibrium between sites located in the coding regions ofthe two genes (as determined by genotyping in the CEU HapMap samples).Recent animal studies show that the IL12RB2 knockout mouse develops anautoimmune/lymphoproliferative disorder with aberrant IL-12 signaling.³⁶Hence, IL12RB2 is a reasonable psoriasis candidate gene. However, thegenetic results presented here seriously diminish the possibility thatIL12RB2 alleles are primarily responsible for the observed psoriasispredisposing effects.

The HapMap project has general population genotype data on both missenseSNPs, rs7530511 (P310L) and rs11209026 (R381Q).³⁵ At rs11209026, the Aallele (minor allele) was found on CEU and YRI chromosomes (8 out of 120CEU chromosomes and 2 out of 120 YRI chromosomes), but not onchromosomes from the two East Asian samples (CHB and JPT). Hence, it ispossible that rs11209026 may predispose some African and/orAfrican-derived populations to autoimmunity and autoinflammatory traits,particularly if the effect size is larger in those subpopulations thanEuropean-derived samples. The rs7530511 SNP is polymorphic in all fourHapMap sample sets, with varying frequencies: 15/120 CEU chromosomes,2/90 CHB chromosomes, 3/88 JPT chromosomes, and 35/118 YRI chromosomes;thereby suggesting that the autoinflammatory effects ascribed to P310Lfor the North American white samples might translate to these otherpopulations. For each of these SNPs, the minor allele in humans appearsto be derived, as many vertebrates including the chimpanzee, macaque,mouse, rat, cow, dog and chicken carry the major allele nucleotides atthe orthologous sites.

These genetic findings coupled with results from multiple areas ofresearch ranging from molecular immunology to clinical biology implicatethe IL-23/T_(H)-17 pathway as being central to chronic inflammatoryconditions such as psoriasis and inflammatory bowel disease; theperturbation of which may disrupt the communication between the innateand adaptive immune responses. In sum, these studies demonstrate severalkey aspects of IL-23/T_(H)-17 pathobiology related to psoriasis: 1) BothIL-12p40 and IL-23p19 mRNA expression levels are significantly elevatedin both non-lesional psoriatic skin versus normal skin as well aslesional psoriatic skin versus non-lesional psoriatic skin.^(37,38) 2)IL-12 and IL-23 knockouts and IL23-deficient animal model experimentsindicate that the systemic inflammatory effects, dermal inflammation andepidermal hyperplasia are often mediated through the IL-23/T_(H)-17pathway^(38,39), 3) T_(H)17 survival and expansion, key characteristicsof epithelial inflammation and epidermal hyperplasia, occur in responseto IL-23⁴⁰⁻⁴² 4) IL-23p19 antibodies inhibit proinflammatory cytokinesin a mouse model of IBD⁴³, and 5) clinical studies have shown dramaticefficacy of IL-12p40 antibodies in reducing symptoms in a highpercentage of psoriatic subjects^(44,45) and those with active Crohn'sdisease.⁴⁶ These diverse studies have conspired to highlight the centralfunction of the IL-23/T_(H)-17 axis in mediating chronic inflammatorydisease pathogenesis, downplaying the role of IL-12. Hence, full geneticdescription of both IL12B and IL23R, genes encoding for criticalproteins in the IL-23/T_(H)-17 response, enables delineation of specificvariants predisposing and protective of disease and facilitates afurther understanding of the molecular pathobiology of autoinflammatoryphenotypes.

Along with psoriasis, IL23R appears to play an important role inpredisposition to other autoinflammatory diseases including IBD(particularly adult and pediatric Crohn's disease)¹⁶⁻²⁴, AS^(25,26), andGO.²⁷ IL23R variants may also underlie susceptibility to celiacdisease²⁸, Graves' disease without ophthalmopathy²⁷ and multiplesclerosis^(25,28,29,30,31) Interestingly, multiple independent IL23Rpolymorphisms have been reported to be associated with AS, GO andCrohn's disease, suggesting a model of allelic heterogeneity within eachdisease where disruption of IL-23R function can occur from severaldistinct genetic insults. With AS, both R381Q and rs1343151 arereplicated SNPs (R381Q was associated with psoriasis in this study). TwoIL23R SNPs, rs2201841 and rs10889677, are associated with GO, and P310Lmay be associated with Graves' disease. R381Q may be the major IL23Rsusceptibility polymorphism for Crohn's disease with the minor alleleconferring protective effects as in psoriasis. rs7517847 plays a role inCrohn's disease, and P310L appears to be significantly correlated withpsoriasis.

The IL23R variants described herein have uses related to targetedtherapeutics, such as the efficacious IL12/23 monoclonalantibodies⁴⁴⁻⁴⁶, and in autoinflammatory pharmacogenetics, for example.

Materials and Methods

Subjects

The subjects in all three sample sets were white North Americanindividuals. Sample Set 1 (also referred to herein as “S0048”) consistedof 467 psoriasis cases and 500 controls, all residing in either Utah orsouthern Idaho. Sample Set 2 (also referred to herein as “S0056A”) wasobtained by the Genomics Collaborative Division of SeraCare LifeSciences (GCI) and included 498 cases and 498 controls. Lastly,BioCollections Worldwide and GCI provided Sample Set 3 (also referred toherein as “A0019”), composed of 481 cases and 424 controls. Detailsconcerning these subjects were previously described.¹¹ All individualsincluded in this study were 18 years or older at time of enrollment. Allprotocols were approved by national and/or local institutional reviewboards, and informed written consent was obtained from all subjects.

Genotyping

Individual genotyping was performed using allele-specific kinetic PCR on0.3 ng of DNA and the resulting data hand-curated prior to statisticalanalyses without knowledge of case/control status. Genotyping accuracyof the laboratory is consistently better than 99%.¹¹

SNP Selection

A multifaceted approach was undertaken to identify SNPs to genotypeindividually in a fine-scale mapping effort in the IL23R region. A 336kbp region was selected across a portion of Clorf141 through SERBP1.This region was delineated on the basis of two criteria: 1) the decay ofLD from the two IL23R SNPs, rs7530511 and rs11209026, originallyidentified to be associated in the sample sets¹¹, and 2) coverage ofclear biological candidate genes nearby—in this case, IL23R and IL12RB2.Next, SNPs were selected in this 336 kbp region to cover two geneticmodels: one of allelic heterogeneity where multiple variants segregatingat the same gene or functional motif independently contribute to diseasepredisposition; and the second model where the association observed atthe originally-identified SNPs, rs7530511 and rs11209026, was driventhrough LD with one or more untyped polymorphisms. To address these twopossible models, SNPs were partitioned in the 336 kbp region into thosein moderate to high LD (r²>0.20) with one of the original two associatedSNPs, and those exhibiting weak LD with the original SNPs (r²<0.20). Thethreshold value of r²=0.20 was determined analytically by solving forthe r² value that would generate the observed results at these twooriginal SNPs from an untyped marker having a reasonable disease model(relative risk below 2.25 with similar allele frequency). The r² valueswere calculated from the HapMap CEU data.³⁵ Next, the tagging SNPprogram Redigo⁴⁷ was ran on those SNPs in weak LD, selecting SNPs withthe highest power to detect an arbitrary disease predisposing site inthe region. Redigo uses a genotype-based approach that maximizes powerto detect disease susceptibility SNPs. All of the SNPs in themoderate-to-high LD group were then selected and this set was reduced sothat SNPs in extremely high LD (r²>0.97) were represented by a singleSNP. Lastly, any SNP with putative functional annotation was selected tobe genotyped. In all, 61 SNPs, inclusive of the two SNPs fully genotypedin the original study, were identified and judged as being sufficient tocover both genetic models for the IL23R region.

Statistical Analysis

Several analyses were performed on individual SNPs. An in-house geneticanalysis application was used to analyze much of the data.Hardy-Weinberg equilibrium testing was accomplished through the exacttest of Weir.⁴⁸ A William's-corrected G-test was used to calculateP-values for genotypic association.⁴⁹ Approximate confidence intervalsfor the odds ratios were calculated using the typical estimate of thestandard error of the log-odds ratio. The Mantel-Haenszel procedure totest odds ratios for homogeneity (test of heterogeneity of effect) wasperformed following Sokal and Rohlf (Chapter 17, Reference 49). P-valueswere combined across sample sets using either the continuity-correctedMantel-Haenszel statistic (eqn 17.22, reference 49) or the Fisher'scombined P-value (omnibus procedure).⁵⁰ Similarly, Mantel-Haenszelcommon odds ratios were calculated to combine data across sample sets.⁵¹A Monte Carlo simulation was written in XLISP-STAT to calculate 95%confidence intervals on the common odds ratios. Typically, 20,000iterations of the Monte Carlo were performed unless results were notsufficiently converging, in which case 40,000 iterations were used.

Pairwise linkage disequilibrium was calculated using either the LDMaxpackage where 2-SNP haplotypes were estimated through an EM algorithmand the standard r² statistic employed,^(52,53) or, in some instances,an r² statistic was calculated using unphased genotype or diplotypedata. Given perfect phasing for the double heterozygotes andHardy-Weinberg Equilibrium, these two methods yield identical values.

Sliding window haplotype association tests were performed by runningHaplo.Stats⁵⁴ sequentially on adjacent sets of three SNPs. Plots of theglobal P-values from each window were plotted against the averageposition of the SNPs in the window. Additional haplotype and diplotypework was performed using the Pseudo-Gibbs sampling algorithm from theSNPAnalyzer program⁵⁵ to estimate phase, followed by aWilliam's-corrected G test of homogeneity.

Similar to the haplotype method⁵⁶, a test of pairwise conditionalindependence (i.e., fixing the genotypes at one SNP and testing for theassociation at a second SNP) was performed through a permutation routinewhere case/control status is permuted against genotype data to generatea null distribution. For conditional independence hypotheses concerningonly a small number of highly significant SNPs driving correlated SNPsto association solely through LD (such as is the case here), apermutation method has advantages over logistic regression models inthat the P-values, given a sufficient number of iterations, will beappropriate regardless of LD levels, effect size and counts.Alternatively, logistic regression-based methods are preferred insituations that warrant inclusion of many SNPs and/or covariates withlow to moderate LD/correlation levels and/or the hypothesis testedrequires adjustment to be performed on more than one SNP. Typically,2,000 iterations of the permutation were performed and P-values werecalculated through a modeling procedure where a log-likelihood ratiotest statistic is calculated for each of the permuted iterations. Next,the parameters of a gamma probability density are estimated from thepermuted log-likelihood ratio test statistics and a P-value iscalculated by integrating this null density from the observedlog-likelihood ratio statistic. For a given number of permutationiterations, this modeling procedure gives more accurate P-values thansimply taking the frequency of those permuted iterations that exceed theobserved value.

Related Material Incorporated Herein by Reference

Garcia et al., “Detailed genetic characterization of the interleukin-23receptor in psoriasis”, Genes Immun. 2008 September; 9(6):546-55; U.S.patent application Ser. No. 11/899,017, filed Aug. 31, 2007 (Begovich etal.); and Cargill et al., “A large-scale genetic association studyconfirms IL12B and leads to the identification of IL23R as psoriasisrisk genes”, Am J Hum Genet. 2007 February; 80(2):273-90, which describethe same sample sets as used here in Example 1, are each incorporatedherein by reference in their entirety.

REFERENCES

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Example 2 Identification and Analysis of Haplotypes and Individual SNPsin the IL12B Region Associated with Psoriasis

IL12B Haplotypes

Using the same sample sets as described above in Example 1 for the IL23Rregion, haplotype analyses were carried out to identify SNP haplotypesin the IL12B region that are associated with psoriasis risk.

The sample sets (psoriasis case and control samples) used for thehaplotype analyses of the IL12B region are described in Example 1 above(“S0048”, “S0056A”, and “A0019” as indicated in Tables 9-10 correspondto “Sample Set 1”, “Sample Set 2”, and “Sample Set 3”, respectively,which are described above in Example 1). The sample sets are also thesame as those described in U.S. patent application Ser. No. 11/899,017,filed Aug. 31, 2007 (Begovich et al.), and Cargill et al., “Alarge-scale genetic association study confirms IL12B and leads to theidentification of IL23R as psoriasis risk genes”, Am J Hum Genet. 2007February; 80(2):273-90, both of which are incorporated herein byreference in their entirety.

Methods were similar to those described above in Example 1, and in U.S.patent application Ser. No. 11/899,017, filed Aug. 31, 2007 (Begovich etal.), and Cargill et al., “A large-scale genetic association studyconfirms IL12B and leads to the identification of IL23R as psoriasisrisk genes”, Am J Hum Genet. 2007 February; 80(2):273-90, both of whichare incorporated herein by reference in their entirety.

For haplotype analyses, the Haplo.Stats program using an EM algorithm(Schaid et al., “Score tests for association between traits andhaplotypes when linkage phase is ambiguous”, Am J Hum Genet 2002;70:425-434) and the SNP Analyzer program using a pseudo-Gibbs samplingalgorithm (Yoo et al., “SNPAnalyzer: a web-based integrated workbenchfor single-nucleotide polymorphism analysis”, Nucleic Acids Res 2005;33: W483-488) were used.

The results of these analyses are shown in Tables 9 and 10.

As shown in Tables 9 and 10, the following haplotypes were identified inparticular as non-risk (protective) haplotypes for psoriasis:

1) rs2546892 (G), rs1433048 (A), rs6894567 (G), rs17860508 (C),rs7709212 (C), rs953861 (A), rs6869411 (T), rs1833754 (T), and rs6861600(G) (naive odds ratio=0.594); and

2) rs1368437 (C), rs2082412 (A), rs7730390 (C), rs3181225 (G), rs1368439(T), rs3212227 (G), rs3213120 (C), rs3213119 (G), and rs2853696 (C)(naive odds ratio=0.639).

As shown in Table 10, the following haplotypes were identified inparticular as psoriasis risk (susceptibility) haplotypes:

1) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439(G), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (T)(naive odds ratio=1.241); and

2) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225 (G), rs1368439(T), rs3212227 (T), rs3213120 (C), rs3213119 (G), and rs2853696 (C)(naive odds ratio=1.346).

Individual IL12B SNPs

In addition to haplotype analysis, analysis of individual SNPs in theIL12B region for association with psoriasis risk was also carried outusing the same sample sets (i.e., the sample sets described in Example 1above and in Cargill et al., “A large-scale genetic association studyconfirms IL12B and leads to the identification of IL23R as psoriasisrisk genes”, Am J Hum Genet. 2007 February; 80(2):273-90, as well as inpatent application Ser. No. 11/899,017, filed Aug. 31, 2007 (Begovich etal.)). In summary, the combined sample sets used in this analysistotaled 1,448 individuals with dermatologist-confirmed psoriasis (cases)and 1,385 “normal” subjects without psoriasis (controls) (these totalsincluded three independent white, North American psoriasis sample sets,as follows: Sample Set 1 (obtained from the University of Utah)consisted of 467 cases and 460 controls, Sample Set 2 (obtained from theGenomics Collaborative Division of SeraCare Life Sciences) consisted of498 cases and 498 controls, and Sample Set 3 (obtained from GenomicsCollaborative and BioCollections Worldwide) consisted of 483 cases and427 control subjects).

105 SNPs were identified as being associated with psoriasis risk(p-value <0.05), and these SNPs are shown in Table 11. Of these 105SNPs, the association of 29 of these SNPs with psoriasis was identifiedby genotyping of the psoriasis sample sets (using the combined total of1,448 cases and 1,385 controls) and the association of the other 76 SNPswith psoriasis was identified based on imputation. This is indicated inTable 11, in which the column labeled “Genotyped or Imputed” indicateswhether the data provided for the given SNP was derived from genotypingof the psoriasis sample sets or by imputation.

Imputation was carried out using the BEAGLE genetic analysis program toanalyze genotyping data from the HapMap project (The InternationalHapMap Consortium). Imputation and the BEAGLE program (including themodeling algorithm that BEAGLE utilizes) are described in the followingreferences: Browning, “Missing data imputation and haplotype phaseinference for genome-wide association studies”, Hum Genet (2008)124:439-450 (which reviews imputation and BEAGLE); B L Browning and S RBrowning (2009) “A unified approach to genotype imputation and haplotypephase inference for large data sets of trios and unrelated individuals”.Am J Hum Genet 84:210-223 (which describes BEAGLE's methods for imputingungenotyped markers and phasing parent-offspring trios); S R Browningand B L Browning (2007) “Rapid and accurate haplotype phasing andmissing data inference for whole genome association studies usinglocalized haplotype clustering”. Am J Hum Genet 81:1084-1097 (whichdescribes BEAGLE's methods for inferring haplotype phase or sporadicmissing data in unrelated individuals); B L Browning and S R Browning(2007) “Efficient multilocus association mapping for whole genomeassociation studies using localized haplotype clustering”. GenetEpidemiol 31:365-375 (which describes BEAGLE's methods for associationtesting); S R Browning (2006) “Multilocus association mapping usingvariable-length Markov chains”. Am J Hum Genet 78:903-13 (whichdescribes BEAGLE's haplotype frequency model); and B L Browning and S RBrowning (2008) “Haplotypic analysis of Wellcome Trust Case ControlConsortium data”. Human Genetics 123:273-280 (which describes an examplein which BEAGLE was used to analyze a large genome-wide associationstudy). Each of these references related to imputation and the BEAGLEprogram is incorporated herein by reference.

Example 3 LD SNPs Associated with Autoinflammatory Diseases

Another investigation was conducted to identify additional SNPs that arecalculated to be in linkage disequilibrium (LD) with certain“interrogated SNPs” that have been found to be associated withautoinflammatory diseases, particularly psoriasis, as described hereinand shown in the tables. The interrogated SNPs are shown in column 1(which indicates the hCV identification numbers of each interrogatedSNP) and column 2 (which indicates the public rs identification numbersof each interrogated SNP) of Table 4. The methodology is describedearlier in the instant application. To summarize briefly, the powerthreshold (T) was set at an appropriate level, such as 51%, fordetecting disease association using LD markers. This power threshold isbased on equation (31) above, which incorporates allele frequency datafrom previous disease association studies, the predicted error rate fornot detecting truly disease-associated markers, and a significance levelof 0.05. Using this power calculation and the sample size, a thresholdlevel of LD, or r² value, was derived for each interrogated SNP (r_(T)², equations (32) and (33) above). The threshold value r_(T) ² is theminimum value of linkage disequilibrium between the interrogated SNP andits LD SNPs possible such that the non-interrogated SNP still retains apower greater or equal to T for detecting disease association.

Based on the above methodology, LD SNPs were found for the interrogatedSNPs. Several exemplary LD SNPs for the interrogated SNPs are listed inTable 4; each LD SNP is associated with its respective interrogated SNP.Also shown are the public SNP IDs (rs numbers) for the interrogated andLD SNPs, when available, and the threshold r² value and the power usedto determine this, and the r² value of linkage disequilibrium betweenthe interrogated SNP and its corresponding LD SNP. As an example inTable 4, the interrogated SNP rs10889677 (hCV11283764) was calculated tobe in LD with rs2201841 (hCV1272302) at an r² value of 0.9325, based ona 51% power calculation, thus also establishing the latter SNP as amarker associated with psoriasis (as well as related pathologies such asCrohn's disease).

In general, the threshold r_(T) ² value can be set such that one ofordinary skill in the art would consider that any two SNPs having an r²value greater than or equal to the threshold r_(T) ² value would be insufficient LD with each other such that either SNP is useful for thesame utilities, such as determining an individual's risk for psoriasis(or related pathologies such as Crohn's disease). For example, invarious embodiments, the threshold r_(T) ² value used to classify SNPsas being in sufficient LD with an interrogated SNP (such that these LDSNPs can be used for the same utilities as the interrogated SNP, forexample) can be set at, for example, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95,0.96, 0.97, 0.98, 0.99, 1, etc. (or any other r² value in-between thesevalues). Threshold r_(T) ² values may be utilized with or withoutconsidering power or other calculations.

All publications and patents cited in this specification are hereinincorporated by reference in their entirety. Modifications andvariations of the described compositions, methods and systems of theinvention will be apparent to those skilled in the art without departingfrom the scope and spirit of the invention. Although the invention hasbeen described in connection with specific preferred embodiments andcertain working examples, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the above-described modes for carryingout the invention that are obvious to those skilled in the field ofmolecular biology, genetics and related fields are intended to be withinthe scope of the following claims.

TABLE 1 Gene Number: 1 Gene Symbol IL12B-3593 Gene Name: interleukin 12B(natural killer cell stimulatory factor 2, cytotoxic 1 ymphocytematuration factor 2, p40) Public Transcript Accession: NM_002187 PublicProtein Accession: NP_002178 Chromosome: 5 OMIM NUMBER: 161561 OMIMInformation: BCG and salmonella infection, disseminated, 209950 (1);{Asthma,/susceptibility to}, 600807 (3) Transcript Sequence (SEQ ID NO:1): Protein Sequence (SEQ ID NO: 3): SNP Information Context (SEQ ID NO:5): AAGACACAACGGAATAGACCCAAAAAGATAATTTCTATCTGATTTGCTTTAAAACGTTTTTTTAGGATCACAATGATATCTTTGCTGTATTTGTATAGTTMGATGCTAAATGCTCATTGAAACAATCAGCTAATTTATGTATAGATTTTCCAGCTCTCAAGTTGCCATGGGCCTTCATGCTATTTAAATATTTAAGTAATT Celera SNP ID: hCV2084293 PublicSNP ID: rs3212227 SNP Chromosome Position: 158675528 SNP in TranscriptSequence SEQ ID NO: 1 SNP Position Transcript: 1188 SNP Source: dbSNP;Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A, 93|C,27) SNP Type: UTR3 Context (SEQ ID NO: 6):CACGGTCATCTGCCGCAAAAATGCCAGCATTAGCGTGCGGGCCCAGGACCGCTACTATAGCTCATCTTGGAGCGAATGGGCATCTGTGCCCTGCAGTTAGRTTCTGATCCAGGATGAAAATTTGGAGGAAAAGTGGAAGATATTAAGCAAAATGTTTAAAGACACAACGGAATAGACCCAAAAAGATAATTTCTATCTGAT Celera SNP ID: hCV2084294Public SNP ID: rs3213120 SNP Chromosome Position: 158675686 SNP inTranscript Sequence SEQ ID NO: 1 SNP Position Transcript: 1030 SNPSource: dbSNP; Celera; HapMap; HGBASE; Population(Allele, Count):Caucasian (G, 117|A, 3) SNP Type: UTR3 Context (SEQ ID NO: 7):TGTCTGGAAGGCAAAAAGATCTTAAGATTCAAGAGAGAGGACAAGTAGTTATGGCTAAGGACATGAAATTGTCAGAATGGCAGGTGGCTTCTTAACAGCCMTGTGAGAAGCAGACAGATGCAAAGAAAATCTGGAATCCCTTTCTCATTAGCATGAATGAACCTGATACACAATTATGACCAGAAAATATGGCTCCATGAA Celera SNP ID: hCV7537839Public SNP ID: rs1368439 SNP Chromosome Position: 158674592 SNP inTranscript Sequence SEQ ID NO: 1 SNP Position Transcript: 2124 SNPSource: dbSNP; Celera; HapMap; HGBASE; Population(Allele, Count):Caucasian (C, 26|A, 94) SNP Type: UTR3 Context (SEQ ID NO: 8):CCACATTCCTACTTCTCCCTGACATTCTGCGTTCAGGTCCAGGGCAAGAGCAAGAGAGAAAAGAAAGATAGAGTCTTCACGGACAAGACCTCAGCCACGGKCATCTGCCGCAAAAATGCCAGCATTAGCGTGCGGGCCCAGGACCGCTACTATAGCTCATCTTGGAGCGAATGGGCATCTGTGCCCTGCAGTTAGGTTCTG Celera SNP ID: hCV31985602Public SNP ID: rs3213119 SNP Chromosome Position: 158676366 SNP inTranscript Sequence SEQ ID NO: 1 SNP Position Transcript: 935 SNPSource: dbSNP; HapMap; HGBASE; Population(Allele, Count): Caucasian (G,115|T, 1) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 3, atposition 298, (V, GTC) (F, TTC) Gene Number: 2 Gene Symbol IL23R-149233Gene Name: interleukin 23 receptor Public Transcript Accession:NM_144701 Public Protein Accession: NP_653302 Chromosome: 1 OMIM NUMBER:607562 OMIM Information: Transcript Sequence (SEQ ID NO: 2): ProteinSequence (SEQ ID NO: 4): SNP Information Context (SEQ ID NO: 9):CTGACAACAGAGGAGACATTGGACTTTTATTGGGAATGATCGTCTTTGCTGTTATGTTGTCAATTCTTTCTTTGATTGGGATATTTAACAGATCATTCCGRACTGGGATTAAAAGAAGGATCTTATTGTTAATACCAAAGTGGCTTTATGAAGATATTCCTAATATGAAAAACAGCAATGTTGTGAAAATGCTACAGGAAA Celera SNP ID: hCV1272298Public SNP ID: rs11209026 SNP Chromosome Position: 67478546 SNP inTranscript Sequence SEQ ID NO: 2 SNP Position Transcript: 1228 SNPSource: dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G,112|A, 8) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 4, atposition 381, (R, CGA) (Q, CAA) Context (SEQ ID NO: 10):TGCAACAGTCAGAATTCTACTTGGAGCCAAACATTAAGTACGTATTTCAAGTGAGATGTCAAGAAACAGGCAAAAGGTACTGGCAGCCTTGGAGTTCACTYTTTTTTCATAAAACACCTGAAACAGTTCCCCAGGTCACATCAAAAGCATTCCAACATGACACATGGAATTCTGGGCTAACAGTTGCTTCCATCTCTACAG Celera SNP ID: hCV2990018Public SNP ID: rs7530511 SNP Chromosome Position: 67457975 SNP inTranscript Sequence SEQ ID NO: 2 SNP Position Transcript: 1015 SNPSource: dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T,15|C, 105) SNP Type: Missense Mutation Protein Coding: SEQ ID NO: 4, atposition 310, (L, CTG) (P, CCG) Context (SEQ ID NO: 11):ATCTTGTTTCCAGAGTAGTGACATTTCTGTGCTCCTACCATCACCATGTAAGAATTCCCGGGAGCTCCATGCCTTTTTAATTTTAGCCATTCTTCTGCCTMATTTCTTAAAATTAGAGAATTAAGGTCCCGAAGGTGGAACATGCTTCATGGTCACACATACAGGCACAAAAACAGCATTATGTGGACGCCTCATGTATTT Celera SNP ID: hCV11283764Public SNP ID: rs10889677 SNP Chromosome Position: 67497708 SNP inTranscript Sequence SEQ ID NO: 2 SNP Position Transcript: 2284 SNPSource: dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C,87|A, 33) SNP Type: UTR3 Context (SEQ ID NO: 12):GAGGAGTTGCCATCTATTAATACTTATTTTCCACAAAATATTTTGGAAAGCCACTTCAATAGGATTTCACTCTTGGAAAAGTAGAGCTGTGTGGTCAAAAKCAATATGAGAAAGCTGCCTTGCAATCTGAACTTGGGTTTTCCCTGCAATAGAAATTGAATTCTGCCTCTTTTTGAAAAAAATGTATTCACATACAAATCT Celera SNP ID: hCV31222798Public SNP ID: rs11465827 SNP Chromosome Position: 67497416 SNP inTranscript Sequence SEQ ID NO: 2 SNP Position Transcript: 1992 SNPSource: dbSNP Population(Allele, Count): Caucasian (T, 117|G, 3) SNPType: UTR3

TABLE 2 Gene Number: 1 Gene Symbol: IL12B-3593 Gene Name: interleukin12B (natural killer cell stimulatory factor 2, cytotoxic 1 ymphocytematuration factor 2, p40) Chromosome: 5 OMIM NUMBER: 161561 OMIMInformation: BCG and salmonella infection, disseminated, 209950 (1);{Asthma,/susceptibility to}, 600807 (3) Genomic Sequence (SEQ ID NO:13): SNP Information Context (SEQ ID NO: 21):GGAAAGTTTTCGGAGTTTTACAGCAAGAAAAACACCATTATGTTTGATGACATAGGGAGAAATTTTCTAATGAACCCACAGAATGGACTAAAGGTAAGACRTACTTTTACTTGTTATGTGCTCATGTAATCTGGGCTGTGTGGTAGAACTTTTGTAGTAAGCACTGTTGAATTTCATATATTTTTGGAAGTACTGTATTCT Celera SNP ID: hCV25633374Public SNP ID: rs12520035 SNP Chromosome Position: 158637948 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 7814 SNP Source:Applera Population(Allele, Count): Caucasian (A, 35|G, 5) AfricanAmerican (A, 29|G, 3) total (A, 64|G, 8) SNP Type: INTRON SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 112|G, 8) SNPType: INTRON Context (SEQ ID NO: 22):TTGGATCTAAATCACAAATATTGGGAAAGGTAAGTTTTAATTGCTTATTTATTTTCTCTTTACATCAATGAAGAAAAAATTATCATTTTTCATCAGTGACYCCAGTATATATATAGCTGTCTTAATTTTTATTTAAAATAGGTGACTTCTAAAAACATTTTCTAATCCAGTGACCTACCCCCAAAAGTATTTTCCCCTTTC Celera SNP ID: hCV7537829Public SNP ID: rs1433046 SNP Chromosome Position: 158642997 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 12863 SNP Source:Applera Population(Allele, Count): Caucasian (C, 10|T, 24) AfricanAmerican (C, 17|T, 5) total (C, 27|T, 29) SNP Type: INTRON; PSEUDOGENESNP Source: dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian(C, 53|T, 67) SNP Type: INTRON; PSEUDOGENE Context (SEQ ID NO: 23):CTGTGTGCCCAGCACTTCCTCTGCATGCCTCAGATGCATTTGACAATCTCAGGTGAACTGCACTTCAGGGTCAAGGGAACCCCGGCCATGGTTCTAAGAARCAACTCCCATTTTAGTATCACCTACATTTGAAACCACAGAGCACTGTCCAGGAGAGGTGATGGTGGTGGGTCTCCTCCTTTGGCTCTCTGGCCCATCAGC Celera SNP ID: hCV1992693Public SNP ID: rs1433048 SNP Chromosome Position: 158688423 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 58289 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (G, 21|A, 99) SNP Type: INTRON Context (SEQ ID NO: 24):ATAAGGGACTGTAGCTCGTCATTTGATGTAGTAGGATATGTAATGATTTAGAAATTTTCATGACACATTTAAGTGAAAGAAGTATTTTAGAGAACACTGTYGTAAGCCGTTAGAAAATAGTTCTTAACCTTTGTTTGGTTCAGGATTACCCTTAATTTAACAAAGAACCTGTCAACTCTCTGAGGCTGCTCTTGTTTATAA Celera SNP ID: hCV2084259Public SNP ID: rs7708700 SNP Chromosome Position: 158636313 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 6179 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (T,26|C, 94) SNP Type: INTRON Context (SEQ ID NO: 25):GCCTAGGCTGGTCTCGAGGTCCTGCACTCAAGCGATCCACCTATCTCGGCCTCTCAAAGTGCAGGATTACAGGCATGAGCCACTGCGCCCAGCCCAGAAAKAGTTCTAAAATGGAGAAATATCCTCAAATGCTGTGTTTTGTTATCATGCTTTCATAATGCACTTGGTAGAAATCTCAAAGATTTCATGTAGATCTTAAAA Celera SNP ID: hCV2084262Public SNP ID: rs17665189 SNP Chromosome Position: 158640194 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 10060 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 53|T, 67)SNP Type: INTRON Context (SEQ ID NO: 26):ATCATATTATCTAAAATTAATTTAAAATTATTGAAAGACTATCTTGAGTTGTATAAAGATATTTGAGCAGGTGTCTTTTACAAAACAGCAGAATTCTTTAYTGAAGCTATAAAATAAGGAAAAGTGCATAAATTTATAGTTCAACAAACTGTAAAGATAATTCTTGTAAAAAATTTTATTCCACTAAAATTACTCATGATT Celera SNP ID: hCV2084263Public SNP ID: rs10515782 SNP Chromosome Position: 158641855 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 11721 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (C, 26|T, 94) SNPType: INTRON; PSEUDOGENE Context (SEQ ID NO: 27):TAAACTCTTTTTCATCATAAAATAGATCAGCCTTAAACATTTGGAAAATATGGCAGTTCTTTTTATGGAAAACTCTTGCATAATTAAAAATGATTTTAACRGAGAATTTAATGATAAAGAAAAATGCTTATGATAAAATGTAGGAGGAAACAGGTTATATAAATGTATAATGATATCTCAGCTATATAAAAATTTAATAGA Celera SNP ID: hCV2084265Public SNP ID: rs7736656 SNP Chromosome Position: 158642268 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 12134 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (A, 26|G, 94)SNP Type: INTRON; PSEUDOGENE Context (SEQ ID NO: 28):TGGAATATAATCCCTCTTCTCATACTGTAACTTAATGTCAGGATAAGATAAAACACATGTAAAAATTTCATAAATAGTATTAAAAATTACCAGTAACTTGWGTGTAGCAGAGAAATTAGAAAAGTTTATCCTACTAAAAAAACAATTACTCATAATTTTCCTTTTTAAAGATAACCACTGTTACCATCTTGGTATATAGTC Celera SNP ID: hCV2084266Public SNP ID: rs10042630 SNP Chromosome Position: 158643346 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 13212 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (A, 26|T, 94)SNP Type: INTRON Context (SEQ ID NO: 29):CAAAGGCCCCCTTCCATTTCTCCTCTCCAGAGTGTTCCAGTAAGAACATCCCCTTCTAGCTATTTCACACATGGACAACCAAGAAATAGTCATTTACAGARCATTTTGCATTTGTACAATTTCACTCGTTATTTCTCCCCCAGTACCTAATGGGGGCTGCAGCGTGTACTCTGTTCGTGGTTAAATTCTGCTGCCAGAAGT Celera SNP ID: hCV2084270Public SNP ID: rs2082412 SNP Chromosome Position: 158650367 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 20233 SNP Source:dbSNP; Celera; HGBASE Population(Allele, Count): Caucasian (G, 93|A, 27)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 30):AGGGGCTACAGGCCCCATGCAATTCTAAAATCCAGCAGAGCAGTCAAATCTTAAAGCTCCAGAATGATCTCCTTCAACTCCATGTCTCACATTCAGGTCAYGCTGAAGTAGGTGCCCGAGGTCTTGGGCAGCTCTGCCCCTGTGACTTTGCAAGGTACAGCCTCTCTCCCGGCTGCCTTCACAATCTGGCATTGAGTGTCT Celera SNP ID: hCV2084272Public SNP ID: rs2116821 SNP Chromosome Position: 158657658 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 27524 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T,47|C, 67) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 31):ATAAAAACTAAAGATAACATCTTGACATATGTCCCTGAGTTATTTTTCAGAAACGCAGACTCCCACCAGATGGAAAATGTTACATAGGCTGTCACACAGAYTGAACTCTGACTGCCATTCCTTGTTCTAATTTTCTTCCTGAGGGGCCTGAAGAAAGTCATGCACACAGTCCAAACCTGAACATTCCTTTCTGTGGACCCC Celera SNP ID: hCV2084274Public SNP ID: rs1433047 SNP Chromosome Position: 158660134 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 30000 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T,26|C, 94) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 32):GAACAGATGACCAGGGGTGACTCAGGACAGAGCAGGTGACCAGGGGAACAGATGTGAACTGCTGATTAGAACTGGTGGAAAAAGTTGTTTACTGAAACTAYGGGCGAGGAGAATGAGGAAGTTAAACTTTAAAATGGAGAACAAAGAACTGAACATACTGACATACTGATTCTTTGAAGAGAAATTTAGAACTCACTGTAT Celera SNP ID: hCV2084277Public SNP ID: rs6874870 SNP Chromosome Position: 158662099 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 31965 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (T, 231C, 93) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 33):CCACTTCCAACATTGGGGATCAAATTTCAACATGAGATTTGGAGGGACAAATATGCAAACCATATCAGGTGTTGATGGTGAAGGGGTGCTGTGTTTCTTTYTGGGGTATTGAAAATATTCCAGAATTTATTGTGGTGATGGGAGCACAACTCTGTAAGTGTATAAAACCTGTTGAATTAGACACCTTAAAAGAGTCACTTG Celera SNP ID: hCV2084281Public SNP ID: rs7730390 SNP Chromosome Position: 158663370 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 33236 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 91|C, 27)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 34):GTGATAATGTCTGGGCTTGGCAATTACCTTCAGTCTGTTCTCCTCCTGTGATACAGTTAATTTTTCCTAATTAATGAGATTCCTGGGGAGGAAACTCATGRCAATTGAGTGCCTTTTTGGAAGATCTATCTTTAGGCAGACGAGGCAAGTTCAGAGACCACCCTTCCCTGTGCTTTTGAAACAGGGGTGAGAGACAGCAGG Celera SNP ID: hCV2084283Public SNP ID: rs1549922 SNP Chromosome Position: 158664126 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 33992 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (G, 63|A, 53) SNP Type: INTERGENIC; UNKNOWN Context (SEQ IDNO: 35): ACCAAGGCCAGGTAAAAACCACCCCTTCATCCCCTAAACCTTGCAAGAAGCACAGGGTCCAGAATTATGCTTCTTTCAGGTTCTAAATAGCACAATAAAAYTAATAACAATAAGCTTTTAGTTATTAGATCAGGTACATTTTACTTTACAGTAAGCTTTTACTTATTGGATCAGGTACATTTTAAAGCAATTTTTGAACAT Celera SNP ID: hCV2084288Public SNP ID: rs6870828 SNP Chromosome Position: 158671090 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 40956 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 54|T, 64)SNP Type: INTRON Context (SEQ ID NO: 36):AATTACTTAAATATTTAAATAGCATGAAGGCCCATGGCAACTTGAGAGCTGGAAAATCTATACATAAATTAGCTGATTGTTTCAATGAGCATTTAGCATCKAACTATACAAATACAGCAAAGATATCATTGTGATCCTAAAAAAACGTTTTAAAGCAAATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTT Celera SNP ID: hCV2084293Public SNP ID: rs3212227 SNP Chromosome Position: 158675528 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 45394 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T,93|G, 27) SNP Type: UTR3; INTRON Context (SEQ ID NO: 37):ATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTTTAAACATTTTGCTTAATATCTTCCACTTTTCCTCCAAATTTTCATCCTGGATCAGAAYCTGGAAGAGAATGCCAAAAGTTGATGTGGGGTGACATTGTAACAGCAATGTCTCTTCTTATTTCTCACAACATATGATCCTGGGCAACTGGGTTTCAGGG Celera SNP ID: hCV2084294Public SNP ID: rs3213120 SNP Chromosome Position: 158675686 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 45552 SNP Source:dbSNP; Celera; HapMap; HGBASE; Population(Allele, Count): Caucasian (C,117|T, 3) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ ID NO: 38):GGAAAATGTCTTAGGTTCTCTGTGTCTGTTTCCTCACTTATAAATAGGGATAACAATAATGCCTACTTCATAGAATTATAGTTCAAGGTAAAAATCACGTYAAACTCTTAGCAAGTCTTTAGCACATAGGAAGCACTCAATATCACCTATTAGTCATACAGATCTTAAATAGGGAAAGTACTTGCCAAGATGTAAAATAAT Celera SNP ID: hCV2084295Public SNP ID: rs2195940 SNP Chromosome Position: 158676930 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 46796 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (C,110|T, 10) SNP Type: INTRON Context (SEQ ID NO: 39):GGCTTTGTCCAGTGATTTTAAAAGTGGGGTGAAAGGAGTCTGGGGCGGTACAAAAGGGCCTCTGGAACCTTGCAACAGGCAAAGGAATTCTGCTGTAAGGYGAGGAAGCTGGGAAGCCAATATCTTAGCCTCTATAAGTGTAGACATTCTGTTTAGTAAAATAATTTTATAATATCTGGAACAGCCAGGAGCTATCCATTT Celera SNP ID: hCV2084296Public SNP ID: rs2853696 SNP Chromosome Position: 158677238 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 47104 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (T, 26|C, 94) SNP Type: INTRON Context (SEQ ID NO: 40):CCCCTCTGACTCTCTCTGCAGAGAGTGTAGCAGCTCCGCACGTCACCCCTTGGGGGTCAGAAGAGCTGAAGTCAAAGACAGAAATTAGCCTGTGTTACACMTTGGGGAGAGAGTTCCTAGTGATTGTAGCCAGTAAGGCAGGTAAGGCCTCAACTGTTGTCTGAGGACACAGTTTCTCCAACTGGGCTGATTTCTACCCAG Celera SNP ID: hCV2084297Public SNP ID: rs919766 SNP Chromosome Position: 158680142 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 50008 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,110|C, 10) SNP Type: INTRON Context (SEQ ID NO: 41):GTCTGCTTCAGGGCCCCTAAGATCTACGCCCTGGAGCTCTTGTTTTTATTTTTGACTCAAGGTGCAATTTCAGCAAGTCATTTGTAGCTTTGAATTCTCCKTTTATCCCTTTCTTTGGTGCTATGAGGCTTCAGGAAGCATGGCCAGGCAATTTGGATGAGTGGGTTCAAACACAGCAGAGACTATTCTCAGTTCCCAATA Celera SNP ID: hCV2084298Public SNP ID: rs2853694 SNP Chromosome Position: 158681666 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 51532 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,65|T, 55) SNP Type: INTRON Context (SEQ ID NO: 42):TATCTGCCTTACATTTGACTGAGGATTAAATGAAAAAAAAAAAAAGCACGTAAAGTACTTAGCACAGTGTCTGCCACACAGTAAATTCGGTGTTAGTTATYGTTACTTATAGACTGAGGAGTCAGCCAACTGTACAGAGAAACTCTCTTAACAATTTTCCATGGATATTTAAGGATTTCGTTCCCTCTGTTTTAAATCACC Celera SNP ID: hCV2084301Public SNP ID: rs3213093 SNP Chromosome Position: 158683557 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 53423 SNP Source:dbSNP; Celera; HGBASE Population(Allele, Count): Caucasian (C, 93|T, 27)SNP Type: INTRON Context (SEQ ID NO: 43):TCCCATGATGGTCAAGGAATAATTTTGGAGGAGACGTTTAACTTTAAAAAAAAAAATACAATCATTAGTTTCATGTTTGTTTAAAAGAAACTTTGTTTTCSTAACCAACATTTGAGCTCCATTCATCTCTTGATGCAGGGAGAGATGTTATTGTAAATGTCTAGTTCTTTATGTTACTTTACAGTAGGGTTTTTAAAAGAC Celera SNP ID: hCV7537756Public SNP ID: rs1368437 SNP Chromosome Position: 158639557 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 9423 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (C, 112|G, 8) SNP Type: INTRON; PSEUDOGENE Context (SEQ ID NO:44): TTCATGGAGCCATATTTTCTGGTCATAATTGTGTATCAGGTTCATTCATGCTAATGAGAAAGGGATTCCAGATTTTCTTTGCATCTGTCTGCTTCTCACAKGGCTGTTAAGAAGCCACCTGCCATTCTGACAATTTCATGTCCTTAGCCATAACTACTTGTCCTCTCTCTTGAATCTTAAGATCTTTTTGCCTTCCAGACA Celera SNP ID: hCV7537839Public SNP ID: rs1368439 SNP Chromosome Position: 158674592 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 44458 SNP Source:dbSNP; Celera; HapMap; HGBASE; Population(Allele, Count): Caucasian (G,26|T, 94) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ ID NO: 45):GGACAGTAGAGGTGCTTTCCTGTGGGATCCCCAATCTCTCCCCGCCTTCAGGTGAGTCCTGCTGATGCTCAGGCTGCCCTTGGAACAGGGACCTTGGCCAYAGTTTCCTTATCTGTAATAATGGGATGAGAATTCCTCCTGCACAGGGTTGTTAGGGACCTCGTGAGGCAGCTTCTATGGCTGCCTTTGGTGCTTAGTTTT Celera SNP ID: hCV11316602Public SNP ID: rs1865014 SNP Chromosome Position: 158671666 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 41532 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 20|C, 94) SNPType: INTRON Context (SEQ ID NO: 46):TTAATGGTTATGGGCCATGCATTGAAGGACCACCCTGTCTGTGCTAATCCCTCACTTTGCACTGAACATGGAACTAAGCTGAGCCTCTCCCTGGGGATGARATGATAGATTTTCTATTTACTGCCCTTTCTTTTGTCTTTTCATAGCTTTTGGTGCGGACATGTCTTGGAGCAGTTACAGTCAATTGTCTCTATGCTCAAT Celera SNP ID: hCV15803290Public SNP ID: rs2421047 SNP Chromosome Position: 158678885 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 48751 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,93|A, 27) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context(SEQ ID NO: 47):GCTCATTTGCTGTTGAGCAGTGGGAGCAACTTGTTGGCCAAGTTACTCGCTGAGCCTCAGTCTCTTTGTCTATAAAATGGACCTAATACTTATCTCAAAGRCTTGTTGGGAAAGGCAATGAGATAACATATTATAGAAGGCAACCAATAACATATTAACTTGAACCTAGAGGAAGAGGTAAGGGAACAATTCGGTATCTGT Celera SNP ID: hCV15894459Public SNP ID: rs2546892 SNP Chromosome Position: 158688053 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 57919 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (G, 103|A,17) SNP Type: INTRON Context (SEQ ID NO: 48):GAGAAACTTCCAGCACAATTTCAGTTTCATAGAGAATACGGCAGGGCACAATATTCAGCAGAGTAACATAGTGGTTAAAAGCTCAGGGTGTCGAGAACAAYGAACCAAGACTGTCATCCTGTCTCCACTAACCAGCTGGGGGATTTGGAACAAGGTATTTCATTATCATGAGCCTCAGTTTCCTCATCTGTAAAATGATAA Celera SNP ID: hCV29927086Public SNP ID: rs3213094 SNP Chromosome Position: 158683347 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 53213 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 93|T, 27)SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO:49): CTCACCTAACTGCAGGGCACAGATGCCCATTCGCTCCAAGATGAGCTATAGTAGCGGTCCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGAMCGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTGTGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCT Celera SNP ID: hCV31985602Public SNP ID: rs3213119 SNP Chromosome Position: 158676366 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 46232 SNP Source:dbSNP; HapMap; HGBASE; Population(Allele, Count): Caucasian (C,115|A, 1) SNP Type: MISSENSE MUTATION; INTRON Context (SEQ ID NO: 50):CCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGACCGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTRTGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCTGTTTCTGCAATGCATACTCTCCCAAAACAAGCCCATCTTGGTCTTAGGGCACTGTGCT Celera SNP ID: hCV27106395Public SNP ID: rs11574790 SNP Chromosome Position: 158676424 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 46290 SNP Source:dbSNP; Celera; HapMap; Population(Allele, Count): Caucasian (G, 110|A,10) SNP Type: INTRON Context (SEQ ID NO: 51):TAAAAATCTGGTTAGTGTTGTTCATTAAATGTCCGTTAAGTACTTTGGTAACTGCAGATGAAAGACCCTGTAGGGGGACAAACACTTGTTATTAACAACCRTATGCTGTCAAGTGTGGGCTTATAACACGGGACCATATGCTCCAAAGGTTGGCAAAGAATGACAGAAGCCACCCACCATTCCTCCAGGCCAGGAGCAGAG Celera SNP ID: hCV27467944Public SNP ID: rs3181224 SNP Chromosome Position: 158673428 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 43294 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (A, 110|G,10) SNP Type: INTRON Context (SEQ ID NO: 52):GTAGTGGCTAGATTTACAATAAAAAGGACAGTCCTGGAGACTATCTTTAAAGAAGAAAAACTCTGCATTGCATGCACTGAAATTAATCGAATGCTAAGAGRTCATGTCGCAAAAGCACTGGGCATGGTGGGAGCCAGAACATCTCACCTCTGCCCCAGGCTGGCCAGAAATTTGGGGAAAGGTCCCAGTTCTCAGTGCTTA Celera SNP ID: hCV27467945Public SNP ID: rs3181225 SNP Chromosome Position: 158673201 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 43067 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (G, 102|A,18) SNP Type: INTRON Context (SEQ ID NO: 53):GCAATGCTCAACTGTTTCAGTCAAATACCTTAAAAATGAGCATTCCTGGGTTGGGTGACGGAATATTGACAAATTACAGCTTTGTCAGAACTGCTACTAASTCTAGGCGGACCTTGCTATGTACTTTATTCCCTTATAAAGTTTGTGAGTGGCAGAGACAGGCCTAGAAGTCAAGCCTTCTTGGACACTGCTCAGTGCTGT Celera SNP ID: hCV27471935Public SNP ID: rs3212217 SNP Chromosome Position: 158687708 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 57574 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (G, 93|C, 27)SNP Type: INTRON Context (SEQ ID NO: 54):TGTGTGCTGGAGCACCCAGAACTGAAGGACTTGGGTTAGGGACAGGAACGGTAATACAGAGGCGAACTTTCAGGTTCTGGCAACGACCTGGTCACCAGCCMTTGCTGTAGGGGTTTAGCTTCTCTTGTTTTCCAAGTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGAT Celera SNP ID: hCV27486507Public SNP ID: rs3212219 SNP Chromosome Position: 158687039 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 56905 SNP Source:dbSNP; HGBASE Population(Allele, Count): Caucasian (C, 89|A, 27) SNPType: INTRON Context (SEQ ID NO: 55):GTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGATAACCTGGAAGCACTGCTACAACAGACGGCTGAGTMCCACCCCCAGAGTGTCTGATTCAGCAGGCATGAGGGCCTGAGAATATGCATTTCTAGAAAGTTTCCAGGGGAAGCAGATGCTGCTGGCGCTAAGACCACA Celera SNP ID: hCV27508808Public SNP ID: rs3212218 SNP Chromosome Position: 158687174 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 57040 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 81|A, 25)SNP Type: INTRON Context (SEQ ID NO: 56):AATGAACAGAAAATGGAAGTGAGGTACAGAGACAGCTTGGTTGGTTACAGCTAGGTGTTTGCTTTATTTGAGCATGGTCTGATCAGTTGGTAACCTATAAYTGATTGGAGGTTTGCTGCTGTGTTTTACTGCTGAGGCTCAGCTATTAGCTACAAAAATATATTAAATTAGCTTTCAGTCAGTTCATACCAAGTTAGGTTG Celera SNP ID: hCV28001193Public SNP ID: rs4921466 SNP Chromosome Position: 158665350 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 35216 SNP Source:dbSNP; HGBASE Population(Allele, Count): Caucasian (T, 112|C, 8) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 57):CTGTATGCCCAGCAAAGGGCTGGTGGCTGGAAGGACATAGCTTTCTGAGTTAGGACTGGAAGGCTTCTGTACATGTCCAAAGTCAACCTTCATATTCATGRGGAGGGAAAAAGAAGTGGGCTTTAGGATTGCCTCTCCTTGTTGGCCTGCTCTGAGAAAAACAATCGCGGGAGGGTGAGGCGGGAGAATCGCTTGAGCCCA Celera SNP ID: hCV29349409Public SNP ID: rs6859018 SNP Chromosome Position: 158669570 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 39436 SNP Source:dbSNP Population(Allele, Count): Caucasian (G, 91|A, 27) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 58):CTCTTATTTTTAAGATGAGAAACTTAAAGCTTAGAGAAGGAATGTGACTTTCTGGATCAACATCTAGCAGTTGTTTATTTAGTGCTTACTACATAAAGAGMACTGGGCTAGAAGCAGTTGAGAGAGAAAAAAAGGGCTTACCTGGATCCCGCTTCCTAGGAGCAAATACTTTTACTCAATAAATATTTATTAAGTCAGTGT Celera SNP ID: hCV30449508Public SNP ID: rs3212220 SNP Chromosome Position: 158686773 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 56639 SNP Source:dbSNP; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (C,93|A, 27) SNP Type: INTRON Context (SEQ ID NO: 59):GGATTACACAAATGTGTGAACAGCAGAAGGTAGAAACATTGAGGGTTATGGTACAGTCTGTTTGCCACAATCCCTGAATCCATTCTTTAAAAAGTTGGTAKAAAAATACCTACTTTAGAGGGTTGTTATGTGAATTCAAAACAAGATAACATATATCGAGTGTTTACGTGGTACCTGGCACATAGTGAGCATTCAATAAAT Celera SNP ID: hCV30557642Public SNP ID: rs10056599 SNP Chromosome Position: 158655488 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 25354 SNP Source:dbSNP; HapMap; ABI_Val Population(Allele, Count): Caucasian (T, 93|G,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 60):TACTACAGGGGAGAACACTGGTGGACAGACACAACCTAAACAAAGTGATCAAAGTTAATTTCACCAGTACTGAGAGACATTGATTTCATGCCCCTCCTGAYGAGATTCACTGAGAAGGGCACAGTATTACTGCTGTAGGATGCTTGACAAAAATGTAGAACCCAAATTTAATCATGAAGAAACATGAGACAAATGTCACTT Celera SNP ID: hCV29619986Public SNP ID: rs10072923 SNP Chromosome Position: 158668354 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 38220 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 93|C, 27) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 61):CCGATAGTGCCCACGGTGAACCCGTATTATTGTTCCTCTATCAGGTAGCTCAATATATATGAAAAGATAGTGGAATCTGCTAGGTGATACAGGTGAGGGARGATCCTTTGATTTGAGTTGATGACAGGAATTCAGCTGAGTCATGTTTTAGGATGCAGGCTCATACCTAGAACCATCTTGAAAGTACCATCTGGGAGCAAG Celera SNP ID: hCV31985608Public SNP ID: rs12652431 SNP Chromosome Position: 158654672 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 24538 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 94|G, 10) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 62):GACTTTTCAGGAATCTAGAGGTAAATCAATTATTTAATTGAATACAAATCCCTCTTACTTTTATTCCCAGTTCTTAATTCTCTGGAGCACTGATTGCTATYACTTCTTGTTGGATAATCTGTGAGGAGAACTGCTGTAGCTTCCTAAATAAGGCTTTTGAAAGAGCCAGTGGTTTGTCAGAAAAACATGTGACTAAAATCC Celera SNP ID: hCV30629526Public SNP ID: rs4921458 SNP Chromosome Position: 158648241 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 18107 SNP Source:dbSNP; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (T,26|C, 94) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 63):ATAGCTTTTCATTTTTTAACTGGGGCCAAAGTTAGTTAATCCACAAGAATGGGGATCCCAGCTGTCATTTTGGTTGATATCACAACTGACGACCAAGACCRTCACAAATATGGGAGCAAGTCTGATTTGTAACATTATTATAATTATGAATCCAATTACTTTAAGGAATGCACGAAAGGCTTTTTAAAAATTTCAATAGTA Celera SNP ID: hDV71045748Public SNP ID: rs6894567 SNP Chromosome Position: 158689546 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 59412 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 94|G, 26) SNPType: INTRON Context (SEQ ID NO: 64):ACAGACCTAGTTAGACCATAGTCCATATTTCAAATATAATTACATGTGCTCATAGCTGAGAACCTTCTCCTGGGATGGATGCATTTCACCAGGTCACTGCYGAAATGTTGTACTTTTATGGATGGTGATGAGGAAGCATCTGTTTTAGGTGTGGTATTTCCTGGAGGCAGAAAACTGCTTGAGTTAGCTCATTCAGTTTTT Celera SNP ID: hCV31985592Public SNP ID: rs7709212 SNP Chromosome Position: 158696755 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 66621 SNP Source:dbSNP; HapMap; ABI_Val Population(Allele, Count): Caucasian (T, 76|C,44) SNP Type: INTRON Context (SEQ ID NO: 65):AAAACATATGGGTTGGGTTATCCACTTCAATGACTGCACATTAAGCAAGAGTATAGTGTACCATGTTTTATTTAACCATTCCTCTGCTGATTATGTCTTTWTGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAATGGTAAAGTCA Celera SNP ID: hDV75439995Public SNP ID: rs3213097 SNP Chromosome Position: 158681257 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 51123 SNP Source:CDX; dbSNP Population(Allele, Count): Caucasian (T, 89|A, 27) SNP Type:INTRON Context (SEQ ID NO: 66):GTGATTCAGATCTGGGATGGGGCTCAGGAACCTGCATTTTAACAATGGAGGTTCTAATGTGGTCATTGGCAGGTTGTTCTAATGTGGGGGCCACATTAGAG /TTAGACCTCTCTCGGAGACAGGCTGTACATGGCCAGCCAGCATTCTGGTAATATGAGCCAAATGCCCATTGACCTAATTTTGGAGAAGAGGTTTATCAACATGTC Celera SNP ID: hDV79877074Public SNP ID: rs17860508 SNP Chromosome Position: 158692783 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 62649 SNP Source:dbSNP Population(Allele, Count): no_pop (G, —|, —) SNP Type: INTRONICINDEL Context (SEQ ID NO: 67):GTTTACAATGAGGATATTTTAGGGAAAGAATACTAATCTAGGTAGTGAATTGCCATAAGTATAAAAACTGTTGACTTGGAAGAAAAGTGGTTATGTTGTCYTTAATGGTTTCTGTTTAAGGCTTGGAGAGAAGTGCTTTTCTTAATATGTACTGCACCAGGTAAAGGTACAAAAATGTATTCTTGAGTCTTGAGAAGAAAT Celera SNP ID: hCV2084260Public SNP ID: rs13153734 SNP Chromosome Position: 158639291 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 9157 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; CeleraPopulation(Allele, Count): Caucasian (C, 98|T, 20) SNP Type: INTRON;PSEUDOGENE Context (SEQ ID NO: 68):CGAAATCAGTTATTGGACTAATGATACCTATAGCAGCTCTTCAGTGTAAAAGGTAAGGAATGGAAAAACAGGTTGTTACAGTAAGCAACTGAAACTTATTYTTTATTCATGGAAAGTAAAATAGTTCCTTGAGAGGAAGAGGAACTACAGGATAGGGACTGGGAAAAAAGGATATGCAAAAAAACGCAGATTAGTTGCATT Celera SNP ID: hCV2084269Public SNP ID: rs6895626 SNP Chromosome Position: 158646681 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 16547 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 26|C, 94)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 69):CCATATCAGGTGTTGATGGTGAAGGGGTGCTGTGTTTCTTTTTGGGGTATTGAAAATATTCCAGAATTTATTGTGGTGATGGGAGCACAACTCTGTAAGTSTATAAAACCTGTTGAATTAGACACCTTAAAAGAGTCACTTGTAGAGTATGTGAACTATACCTCATTACAGCTGTTAGAAAAATGTATACCTTGGTGGTCA Celera SNP ID: hCV2084282Public SNP ID: rs2099327 SNP Chromosome Position: 158663429 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 33295 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; Celera;HGBASE Population(Allele, Count): Caucasian (G, 100|C, 20) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 70):AATATCTGATTGTGTTACTTCCTTGCTGAAAACCCTTCAGTGGGTTTCAGGGCCCGGGGCCCCCAGAACAAGATTCTGAGTCCTGCAAGCTTGCAAGTCCKCCATGCTCTGCCTCCTGGCTACCTCTCTCTTTTCTTTGCCTTTCTCTTTAGGAGGCCAGAACCCCGGTCTGTTTTCTTTCCTGCAATATCCCTGTGGCCA Celera SNP ID: hCV15824051Public SNP ID: rs2853697 SNP Chromosome Position: 158675981 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 45847 RelatedInterrogated SNP: hCV15894459 (Power = .51) Related Interrogated SNP:hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap; HGBASEPopulation(Allele, Count): Caucasian (T, 102|G, 18) SNP Type:TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 71):TGGAGGTTAACATCAATTAACATCAATAAGAGACTTGATGTTAATTCATTACACTCACCATGACTTGGCTTTTCAATTTGTTGTTGTTGTTGTTTTTAACYCTTATGAGCGAAAGAGAAAATTGATACTATCCAAGGGTATAGAATTACCTTTCTGGTCCTTTAAAATATCAGTGGACCAAATTCCATCTTCCTTTTTGTG Celera SNP ID: hCV15879826Public SNP ID: rs2288831 SNP Chromosome Position: 158682591 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 52457 RelatedInterrogated SNP: hCV2084270 (Power = .51) Related Interrogated SNP:hCV2084293 (Power = .51) Related Interrogated SNP: hDV71045748 (Power= .51) SNP Source: dbSNP; HapMap; ABI_Val; HGBASE Population(Allele,Count): Caucasian (T, 91|C, 25) SNP Type: TRANSCRIPTION FACTOR BINDINGSITE; INTRON Context (SEQ ID NO: 72):TGAAGCAGTCCAGTAGAGCTTAGTCTTCCCATTTAATGAAGAAGCGTACTGAGGCCAACGATCTAAGCATGGTCACAGCAAGTCAGAAGTACAAGGGCTAYAGCTCAGACCTTTTGTCTCTTGGGCTTTGCAAGGGATGCCTAATGCTAGTGTCTAAACTGGCCTTTGAGGAATGGCTTAGTATAGTATTTCAGAGTGTGT Celera SNP ID: hCV16044033Public SNP ID: rs2569254 SNP Chromosome Position: 158683827 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 53693 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap;HGBASE Population(Allele, Count): Caucasian (C, 102|T, 18) SNP Type:INTRON Context (SEQ ID NO: 73):TCACAAGTCTGTTATGTAACCATAGTTGGGACTGGAGTCTGCTCCTCTGATTCCCAGTCCTAAGATCTTTGGCTTAGACATTTAGTACATTTTGTAGTGGSTAGATTTACAATAAAAAGGACAGTCCTGGAGACTATCTTTAAAGAAGAAAAACTCTGCATTGCATGCACTGAAATTAATCGAATGCTAAGAGGTCATGTC Celera SNP ID: hCV27467946Public SNP ID: rs3181226 SNP Chromosome Position: 158673108 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 42974 RelatedInterrogated SNP: hCV15894459 (Power = .51) Related Interrogated SNP:hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap; ABI_Val; HGBASEPopulation(Allele, Count): Caucasian (G, 102|C, 18) SNP Type: INTRONContext (SEQ ID NO: 74):TTATGTCTTTATGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAAWGGTAAAGTCAGGATGATCACCTGGGGTTTGCTTCGGTGATGATTAAAGTAAGCCACATGGGGGTTAACACATAGGTCTTGTATTTATGGAAGTTGCTTTC Celera SNP ID: hCV32389155Public SNP ID: SNP Chromosome Position: 158681347 SNP in GenomicSequence: SEQ ID NO: 13 SNP Position Genomic: 51213 SNP Source: HGBASE;dbSNP Population(Allele, Count): no_pop (A, —|T, —) SNP Type: INTRONContext (SEQ ID NO: 75):TCTGGCGAATTCTACGTGAAATGTCAGGAACCAGTGAAGGGTGTTAAGCATAGAATGACAATCTAATTTTTTTTAACAGCCTTATTGAGATAGAATTTACMTATCACAAATTTACCCATTTGAAGTGTGCAGTTCAATGGTTTTTAGTGTATTTAGAGAGCTGTACAACCATCACTGTAAGCTAATTTTAGAACCTGATTT Celera SNP ID: hCV31985611Public SNP ID: rs13161132 SNP Chromosome Position: 158649646 SNP inGenomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 19512 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (A, 88|C, 16) SNP Type: INTERGENIC;UNKNOWN Gene Number: 2 Gene Symbol: IL23R-149233 Gene Name: interleukin23 receptor Chromosome: 1 OMIM NUMBER: 607562 OMIM Information: GenomicSequence (SEQ ID NO: 14): SNP Information Context (SEQ ID NO: 76):TCTGGCAAAGAGAAGGCCACACACCAGGAAGCCCCTGAGGGTACAGGGACATTACTGATTATAAAGGAGGGAAGGAACAAGCTATGTGTGTTCCTGATAAMCCCTGGCCCTCGGGATTGGCTGTCAAGGGGCTCAAAACCCAGTCCAAGGGACAAACACATCATCCAAGCCTTGCAATGCAGTGATGTAAGTGCAATGATA Celera SNP ID: hCV261080Public SNP ID: rs10889675 SNP Chromosome Position: 67494804 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 100047 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (C,105|A, 15) SNP Type: INTRON Context (SEQ ID NO: 77):TTAGACAACAGAGGAGACATTGGACTTTTATTGGGAATGATCGTCTTTGCTGTTATGTTGTCAATTCTTTCTTTGATTGGGATATTTAACAGATCATTCCRAACTGGGTAGGTTTTTGCAGAATTTCTGTTTTCTGATTTAGACTACATGTATATGTATCACCAAAATTTAGTCATTTCAGTTGTTTACTAGAAAAATCTG Celera SNP ID: hCV1272298Public SNP ID: rs11209026 SNP Chromosome Position: 67478546 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 83789 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 112|A, 8)SNP Type: MISSENSE MUTATION; ESE; INTRON Context (SEQ ID NO: 78):AACTCCTGGACTCAAGAACTCTGCCCACCTTGGCCTCCCAAAGTGCTGGGCTTACAGGCAGGAGCCACCATGCCTGGCCTATGATTATGCTTTTTCTTGARGTCATCATCTTCTATATTAGTTTCCTATTACTACTGTCACAAATCATCACAAACTTGAAAGCTTAAAACAACATGAATTTATTATCTTATAGTTCTGGAG Celera SNP ID: hCV1272302Public SNP ID: rs2201841 SNP Chromosome Position: 67466790 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 72033 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,87|G, 33) SNP Type: INTRON Context (SEQ ID NO: 79):GACTAGAAATTGAGGCTATACCTGCAATGGGAGCAATGTACCTGCCTTTGTCCCAACTCAGGGGAAAAATTCAAGCTGCTTTATCACAATGCAAACTTCGYGGGGGAGAAAGGGTTTCTTTCTATAATTCTTGTATTCAAGAAGGATTCATTGAACTACTGAATGTCCTTACTGTTATATGTGCAAGGCCATTTGAAGGAT Celera SNP ID: hCV2720250Public SNP ID: rs4655531 SNP Chromosome Position: 67500366 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 105609 SNP Source:Celera; HGBASE; dbSNP Population(Allele, Count): no_pop (C, —|T, —) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 80):AATTGAACCCAGGCCACCACTGTGAAAGTAAAAAACTTTAGCTACTGAGCTACAGTACTGGGTAGTCTCCATTGTGCTTCCCAGAAGGGCTCTAAAGTACKTAATTTTGAGCTTGCAAAAGCTTTTAACTACTCAACTTAATTTTTAGAGCTAACTGTGACATGAACCCTAAAATTCCTGTTCCCTTGAAGGCAGAGACCA Celera SNP ID: hCV2720255Public SNP ID: rs10889674 SNP Chromosome Position: 67490116 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 95359 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (G, 43|T, 77) SNPType: INTRON Context (SEQ ID NO: 81):TATTATTATCTCTATTTTCCAAAAGAGAAAACCTGAGACTCAGCAAGTTCATAATTATGCCCCAAGGTCACAGAGCTGATAAGAGGCAGAGTTTAATTCAMACCCAGGTATATCAGGCCACGCTCTTGGTCATTCTGCTCTACTGCTTAGACCCCTTTGCCGAGCACTGTGTTGACCTGAGGGCTGTCTATCCTCTTCCAG Celera SNP ID: hCV2989999Public SNP ID: rs1343152 SNP Chromosome Position: 67476920 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 82163 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,74|C, 42) SNP Type: INTRON Context (SEQ ID NO: 82):GTGCAACAGTCAGAATTCTACTTGGAGCCAAACATTAAGTACGTATTTCAAGTGAGATGTCAAGAAACAGGCAAAAGGTACTGGCAGCCTTGGAGTTCACYGTTTTTTCATAAAACACCTGAAACAGGTGAGTGTACTTATATATTTTATTCTGTTGGGCTTTTCTTTATATATCTTTTCTGCTGAGCACAGTGGCTCACA Celera SNP ID: hCV2990018Public SNP ID: rs7530511 SNP Chromosome Position: 67457975 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 63218 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 15|C,105) SNP Type: MISSENSE MUTATION; ESS; UTR5 Context (SEQ ID NO: 83):GTGCAATCTCGGCTCACTGCAACCTCCATCTCCTGGGTTCAAGTGATTCTCATGCCTCAGCCTCCCAAGTAGCTAGGAATACAGGCACACACCACCATTTSCAACTAATTTTTATATTTTTGGTGGAGACGGGATTTCACCATGTTGGCCAGGCTGCTCTTGAGCTCTTGGCCTCAAGTGATCTGCCTGTCTTTGCCTCCC Celera SNP ID: hCV8367042Public SNP ID: rs1008193 SNP Chromosome Position: 67492499 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 97742 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,82|C, 38) SNP Type: INTRON Context (SEQ ID NO: 84):TTGAGTATTTCTAAGCTGCTCGATAGATTAGAGTTGTTTGGTGTGGCAGTTCCCCAGTGTGTCCAGTTGCTCACAAATTTTGACTTGAATGTTCTTTGCCRAATTGGCACTGAGTTTCTCCTTCTTGCCATCATTTGCTTCATGAAATAATCTTTCTTTCGTTTACATTTATAATCAAGTGCAGTAGAAAGATTTTAAATG Celera SNP ID: hCV8367043 PublicSNP ID: rs1343151 SNP Chromosome Position: 67491717 SNP in GenomicSequence: SEQ ID NO: 14 SNP Position Genomic: 96960 SNP Source: dbSNP;Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (G,73|A, 47) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context(SEQ ID NO: 85):GCAAGACCCTGTCTCAGGAAAAAAAAAAAAAAGAGGAAAAAGAAGAAAAAGAAAAAGAAACATGAAGAAAGGTAAGGGCACTCTGAATTATCAATCAATTRCAAGCCAAGTGCTTAGGTTCAGTACAGTTCCCTAATTATAGATGCCTACACAGACCTACCTACACCTTGATATTTCTGTGGGATCAGTGGAGGTTAGGAA Celera SNP ID: hCV11283754Public SNP ID: rs10489628 SNP Chromosome Position: 67476695 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 81938 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (G,66|A, 54) SNP Type: INTRON Context (SEQ ID NO: 86):ATCTTGTTTCCAGAGTAGTGACATTTCTGTGCTCCTACCATCACCATGTAAGAATTCCCGGGAGCTCCATGCCTTTTTAATTTTAGCCATTCTTCTGCCTMATTTCTTAAAATTAGAGAATTAAGGTCCCGAAGGTGGAACATGCTTCATGGTCACACATACAGGCACAAAAACAGCATTATGTGGACGCCTCATGTATTT Celera SNP ID: hCV11283764Public SNP ID: rs10889677 SNP Chromosome Position: 67497708 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 102951 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 87|A, 33)SNP Type: UTR3 Context (SEQ ID NO: 87):AAAATCCATTGCTGTAGAGGTCAGACACACTCTTTAAGAGAAGGAAGTGTCATCATAAAAGACAACATAGGGAATGGACAGAAAATGTGGACAGAAAGGCRGAGTGGATATGATTGCCCAAGCCATTGAAACGGGAGAGTTCCCTGACTCCTGTCGCATATCATGTGGCTCATCTATTCTGCCAAGGCACATGCTCAAACC Celera SNP ID: hCV27952715Public SNP ID: rs4655692 SNP Chromosome Position: 67464253 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 69496 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (A, 25|G, 93)SNP Type: INTRON Context (SEQ ID NO: 88):CAGCCTAAATTTTAGGGCTTTATTATATAACATTCTCTTTTTAAATATGCGGTAGTTACGGTCACCTTGGAAAGTTCTACAAAATATCCCTTAAGTTTTTYGAACTTTCCCACATGGGAATCTTCTGGTTATGAGAGTTTGCTCTATTTAATATGTGTACGGTTTCACTGCTAGGGTGGTTCTCCCACTTATCTTGAATCT Celera SNP ID: hCV30243123Public SNP ID: rs6693831 SNP Chromosome Position: 67493455 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 98698 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 30|C, 90) SNPType: INTRON Context (SEQ ID NO: 89):ACTCTATAACTGCCTAGCAAGATTATGCAAATTGATAACTACCATTTATCATTTACGAAGTACTCCTGTGTATAAGCTTGTTTGATTATGATGTCAGCCAYATTTGGTAGTGTAATTAGCGCTACTTTACAAAAGCGGAAACTGGGCATGACTTACTAAATAGTACATTGCTGGTGGGTAATGACACCTAAACTATAACAA Celera SNP ID: hCV30279129Public SNP ID: rs10489629 SNP Chromosome Position: 67460937 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 66180 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 58|C, 62) SNPType: INTRON Context (SEQ ID NO: 90):AATCAGTATGATTGTAACCAGCTTTAGACATTGTTACAGCAATTGGGAATTCTCACCTGTGTCAGACAAGCCAAATGAAGCTCACCACTAAGAATTTATAYGAAATTTGCATGCACAAGCCGACCACATTTGCCAGAGATGCACTTCTAAAAACCCACTGACATCAGATACATGTAGCCCAACTTTCTCAAACAAAAAGTT Celera SNP ID: hCV31222826Public SNP ID: rs10789229 SNP Chromosome Position: 67478162 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 83405 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (C, 50|T, 62) SNPType: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 91):ACCCACTGACATCAGATACATGTAGCCCAACTTTCTCAAACAAAAAGTTGTTTCCTGGGGTAGTTGTGCACTCTGGAAAAACAGTCACTCTGTGGCCTAARGTAAAGGTTAATTTTGCTTCCCCCCACCCTTTCTCCTTTGAGACCTTTGCTTTGAGCAGAGTAAAGAGAATAGTAATTCTGGTATCAAATGAAGACTAAT Celera SNP ID: hCV31222825Public SNP ID: rs10889671 SNP Chromosome Position: 67478314 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 83557 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 14|G, 106) SNPType: INTRON Context (SEQ ID NO: 92):GGTTGAAGTATGGTCCACTGGGATTGGCCAAGACTCAGTTACTGTTACAGGCACATACTCCTAAGTCAGGTTTTCACTCTTGTCTGCCTGTTAAGTTAGGWTACAGTTCATCCACAGGGATTCAAATATAGAGGTATGAAGTCCTTCTCAGGCCATATTTAGTTTGCTTTAACACTTGAATTCCACCCAAACAAATCAGCT Celera SNP ID: hCV31222811Public SNP ID: rs12085634 SNP Chromosome Position: 67491301 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 96544 SNP Source:dbSNP Population(Allele, Count): no_pop (A, —|T, —) SNP Type: INTRONContext (SEQ ID NO: 93):ATGACACATGGAATTCTGGGCTAACAGTTGCTTCCATCTCTACAGGGCACCTTACTTCTGGTAAGAAAATACAACTTAGGCTTTTTGAGTAGTCTTTTAGKAATTGCCCATTTTAACCCATCATACTGAAAAAATCACATCAGGTGTTAAGTTTCTGGACAATAAGATATGCCTTATGTCTTCCATAGGAAAATAATAGAC Celera SNP ID: hCV31222838Public SNP ID: rs11465804 SNP Chromosome Position: 67475114 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 80357 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 111|G, 9) SNPType: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 94):GAGGAGTTGCCATCTATTAATACTTATTTTCCACAAAATATTTTGGAAAGCCACTTCAATAGGATTTCACTCTTGGAAAAGTAGAGCTGTGTGGTCAAAAKCAATATGAGAAAGCTGCCTTGCAATCTGAACTTGGGTTTTCCCTGCAATAGAAATTGAATTCTGCCTCTTTTTGAAAAAAATGTATTCACATACAAATCT Celera SNP ID: hCV31222798Public SNP ID: rs11465827 SNP Chromosome Position: 67497416 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 102659 SNP Source:dbSNP Population(Allele, Count): Caucasian (T, 117|G, 3) SNP Type:MICRORNA; UTR3 Context (SEQ ID NO: 95):TAGAAGTGGCTCTGTTTCAAGCTCTGGTAAGCCTATTAGCTAACTCTTTCCCCAACCTCATGTCATCTGAACAAAGGGTTTCTAGGCTAAAAATAAAATAMTTTTTAAAAGTTCAAAAACAACTGGTCAACAGAATAGAGTCTGAGTTCTGTAACACAAGACTTCTGTGATCTGATCCACTCACCATTCCAGCTTTACTCC Celera SNP ID: hCV261079Public SNP ID: rs10889676 SNP Chromosome Position: 67495155 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 100398 RelatedInterrogated SNP: hCV11283764 (Power = .51) Related Interrogated SNP:hCV1272302 (Power = .51) SNP Source: Celera; dbSNP Population(Allele,Count): no_pop (A, —|C, —) SNP Type: INTRON Context (SEQ ID NO: 96):ACATTTTTTTTCAATTTCATGGAAAAGAGGTTTTTCATTTTTCCAAAAATTGTACCAAGGTAAAGCAAAGTTCTAGTTGATGCAGGTGCATTGTATAGGCRTTAGCAATACTGCCCTCATTATGCACTCATTAGACAGTAGTGCAACCCCAAGAAAAGGATGGTTAGATATTTCTTTATAGCAATGCAAGAACAGCCTAAC Celera SNP ID: hCV2720226Public SNP ID: rs2863209 SNP Chromosome Position: 67505934 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 111177 RelatedInterrogated SNP: hCV31222786 (Power = .51) SNP Source: dbSNP; Celera;HGBASE Population(Allele, Count): Caucasian (G, 12|A, 106) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 97):ATTGAAAAGAAGCAGAGCAATAGAGATGAGAGGAAAATCTGAAAAGATAATGACACAATTTCCCACTTAATTTTCATTAAGTAAGAGATGAAAACTTTAGMCTCGGCATCAGGAAGTTTGATTTCTTTAATTAATTTTTTTTTTGAGTCAGGGTCTCACTCTGTTGCCCAGAGTGAGTGCAGTGGCATGGTCACAGCTCAC Celera SNP ID: hCV2720251 PublicSNP ID: rs11465817 SNP Chromosome Position: 67493685 SNP in GenomicSequence: SEQ ID NO: 14 SNP Position Genomic: 98928 Related InterrogatedSNP: hCV11283764 (Power = .51) SNP Source: dbSNP; Celera; HapMapPopulation(Allele, Count): Caucasian (C, 66|A, 42) SNP Type: INTRONContext (SEQ ID NO: 98):CCTTGAAGTCACTTCTGTCAGCTTTTAATTATCAGGAAGGAGGAGACTGGCAAGGCTGCACCAGGACCCCTTTGAGTTCAGACTGAAAGTTAGGTACCAGKGTTGCTCACCCCACCCTGGTCAGAATCATTCATTAGCAGTTTCCTGACAGCCTTTATAACTAGACCAGGCTGCCAGGAAAAGAAAAGAGCAGAGAGAAGT Celera SNP ID: hCV2990001Public SNP ID: rs12030948 SNP Chromosome Position: 67474353 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 79596 RelatedInterrogated SNP: hCV2989999 (Power = .51) SNP Source: dbSNP; Celera;HapMap Population(Allele, Count): Caucasian (G, 78|T, 42) SNP Type:INTRON Context (SEQ ID NO: 99):CTAAATAAATAAATAAATAAAGTAAAATAAAGATAAAAGTCTTAAGCTTCAGGTAGAAGGAAATAGGAACACCACAGTTTAAATTTAAGGTCTGTTTCCTRAGGAGAAAAATCACTTAAGAGACAAAAATACCAATTAAAATTAAGTATCCCTGAAAACTTGGATTTATTAAAGTTTAACATGTTAGCTAAGAGAAACCAT Celera SNP ID: hCV2990015Public SNP ID: rs7528924 SNP Chromosome Position: 67461624 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 66867 RelatedInterrogated SNP: hCV27952715 (Power = .51) SNP Source: dbSNP; Celera;HapMap; ABI_Val Population(Allele, Count): Caucasian (G, 25|A, 95) SNPType: INTRON Context (SEQ ID NO: 100):CAGCACTTTGAGAGGCCAAGGCAGGAAGATTGCTTGAGCCTAGGAGTTTGAGACTGGCCTGGGCAACATAGTGAGACCCTAGTCTGTACAGAAAAATAATMATTATTATTAGCCTGGGTGGTAGAATGCATTTGTAGTCGCAGCTACTTGGGAAGCTGAGGTAGTAGGATTGCGTGAGCCCGGGAGTTTGATGCTGCAGTG Celera SNP ID: hCV2990016Public SNP ID: rs11465802 SNP Chromosome Position: 67458186 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 63429 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (A, 89|C, 31) SNPType: INTRON Context (SEQ ID NO: 101):ATGTCAAGAAACAGGCAAAAGGTACTGGCAGCCTTGGAGTTCACTGTTTTTTCATAAAACACCTGAAACAGGTGAGTGTACTTATATATTTTATTCTGTTRGGCTTTTCTTTATATATCTTTTCTGCTGAGCACAGTGGCTCACACCTATAATTCCAGCACTTTGAGAGGCCAAGGCAGGAAGATTGCTTGAGCCTAGGAG Celera SNP ID: hCV2990017Public SNP ID: rs7518660 SNP Chromosome Position: 67458031 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 63274 RelatedInterrogated SNP: hCV30279129 (Power = .51) SNP Source: dbSNP; CeleraPopulation(Allele, Count): Caucasian (G, 55|A, 59) SNP Type: INTRONContext (SEQ ID NO: 102):GTAATCTATCACACATGAAAAAAGCTTTTATCAAGCTTAAAGGATTACAGCATTGTTTGATCTTCTGCAAATGTTTCCACTGCAGCGAGTGCCTCCTTTTYGCCCCCTAGAGTGGGAAGGAAGCTGCTTTCTCATTCTGTGGTGTCTTAACCCACATCACTATTCAGCACAAAGGAGACACTTCTGATTCTGTCTTTGCCA Celera SNP ID: hCV11728628Public SNP ID: rs2000252 SNP Chromosome Position: 67500143 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 105386 RelatedInterrogated SNP: hCV8367042 (Power = .51) SNP Source: Celera; HGBASE;HapMap; dbSNP Population(Allele, Count): no_pop (C, —|T, —) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 103):ACTCCAGCCTGGGCAATAGAGCGAGACTCCATCTCAAAAAAAGCAGTGTGTGTTTCAGTTTTAATGTATTTCAGAGACAGTATTTGATTATGTACGGCCAYGTTTTATATAAAGAACACTTTGTTTTCCTAGAGTCTAGAAGACAGCTTGGAACATAATAGGTGTTCCATACATTTCTGCTAAATAAAATAGTTGTTTTAA Celera SNP ID: hCV16078411Public SNP ID: rs2863212 SNP Chromosome Position: 67457704 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 62947 RelatedInterrogated SNP: hCV2990018 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (C, 12|T, 108) SNP Type: INTRONContext (SEQ ID NO: 104):TGAGCAAAGCCCCTGTCTTCATGGAGCTTCTATTCTAGCCAGACAGGGCAGAAAAACAGCAAACAAAACAAGAAGAAAAGTCAGGTGGTGGTGAAGTGTCRTAAAGAAACATGAAGTGGGTAGGCATGGTGGCTCACATTTTGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGCAGATTGCTTGAGTCCAGGAGTTTGAG Celera SNP ID: hCV27868367Public SNP ID: rs4655530 SNP Chromosome Position: 67476319 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 81562 RelatedInterrogated SNP: hCV2990018 (Power = .51) Related Interrogated SNP:hCV31222825 (Power = .51) SNP Source: dbSNP; HapMap Population(Allele,Count): Caucasian (G, 14|A, 106) SNP Type: INTRON Context (SEQ ID NO:105): TCCTTTTCTTCTGTCCTTCTCTGCCGAGCCATTCTGCCATTCTTCTGCTCTTCTATTTATCTCTCTGTCTGCTTCTGGAACCTGGGGTCTGGAGTTTATGWGGGTACAGGATAGCGGGGCATAGCAGGCCAAAAGGCAACTTTTGAGCACGAAAACAAGAATGCCTGCTTCTATTTAGGGCTATGGGTTTCCAAGCTTGAG Celera SNP ID: hCV27868368Public SNP ID: rs4655693 SNP Chromosome Position: 67464874 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 70117 RelatedInterrogated SNP: hCV2990018 (Power = .51) Related Interrogated SNP:hCV31222825 (Power = .51) SNP Source: dbSNP; HapMap; HGBASEPopulation(Allele, Count): Caucasian (A, 15|T, 105) SNP Type: INTRONContext (SEQ ID NO: 106):TTTGCAATTCTAGAATCGGACAACACCTCATACTATAAAACAGAGTGAGTGTTCTGATGAGCTGAGCAGAGGAGGTTGATTTAAGGAACTTTCTTATCACRCTGGCGAAAACTGGCCTGTTTAGGGATTTGGCTGTTATCTCTGTGTCCTGATTTGTTGAAAGGTCAGATAAAGATCTTAGTTTCAGCAGGTTAGTGTGGA Celera SNP ID: hCV30423493Public SNP ID: rs7539328 SNP Chromosome Position: 67505191 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 110434 RelatedInterrogated SNP: hCV31222784 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (G, 76|A, 42) SNP Type: INTERGENIC;UNKNOWN Context (SEQ ID NO: 107):ATTCCAATGTGATAAGTAATGCCTCAACTATCTTCTATATTTGAAAATAGGGCTTTTTCATGTACCAGGGAGAAAGCATGATGAGCCTGGTGGGTAATATRTGTTGAATAAATTATATTAATTATTTAAATATTTTAGGAGATTAACTCAACTTTGACATGCAAGAAAAGCATTGGTTTTGTTTGTTTGTTTGTTTGTTTT Celera SNP ID: hCV31222830Public SNP ID: rs12751814 SNP Chromosome Position: 67477451 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 82694 RelatedInterrogated SNP: hCV31222826 (Power = .51) SNP Source: dbSNPPopulation(Allele, Count): Caucasian (G, 50|A, 66) SNP Type: UTR5;INTRON Context (SEQ ID NO: 108):CCCTTATAAATATTTAAATGTCCAATCAGGTAGCCAAATGTACCTGAAGCTTTGATTGTTTTCCCAGGAATATGGGTTTGACAAGCCAAATATTGTTTATRACTATTTTAGTAGTTTATAAGTCACCACACAAACATATTTAATTTGGATCATTTTATCTTTTCCATTACAAGTCGTAAAATGCAGAACTTTTAATAATGA Celera SNP ID: hCV29503362Public SNP ID: rs6682033 SNP Chromosome Position: 67481258 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 86501 RelatedInterrogated SNP: hCV8367042 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (A, 82|G, 38) SNP Type: INTRONContext (SEQ ID NO: 109):CTTACCTATCTTGTGCTAGGACTTGTCTAGACATCTTCTTCAATCTTTAAAACAACCCATGAGATAAGTGTTACGCATCTATTTTATAATGAGGAAACTGMAACTTAGAGTAGTTGAGGAAACTTTTCAAGGTCATAGAGCTGCTAAGTGACAGACTAAAATTCAAATCCTTTTCTTTCAATGTCCTGGAGTCTATTGTCT Celera SNP ID: hCV31222834Public SNP ID: rs11465810 SNP Chromosome Position: 67475773 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 81016 SNP Source:dbSNP Population(Allele, Count): Caucasian (A, 81|C, 39) SNP Type:INTRON Context (SEQ ID NO: 110):AGGTCATTTCCATTTTATCCATTATCAATAAACTTCTTTGCATAGCTTTGTATATAAATGGTCTTTATTCCTTTAGTTCTAAAGAAGAATTATTGCATCARGAGTTAAGCACCTTTTAAGATGCTGATGTATGTTGTCGAACTGCTTTTTACCGAATCTTTAATATTGATTGCTTTTTAAAAAGGGACCTATGAAAAGACA Celera SNP ID: hDV81067815Public SNP ID: rs41396545 SNP Chromosome Position: 67462196 SNP inGenomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 67439 RelatedInterrogated SNP: hCV8367043 (Power = .51) SNP Source: dbSNPPopulation(Allele, Count): no_pop (A, —|G, —) SNP Type: INTRON GeneNumber: 3 Gene Symbol: RNF145-153830 Gene Name: ring finger protein 145Chromosome: 5 OMIM NUMBER: OMIM Information: Genomic Sequence (SEQ IDNO: 15): SNP Information Context (SEQ ID NO: 111):TAATCAAGAATCTTTCAGATGCTCCTAATTGGGCTGAAAATAGCAGCTGTTTTGAAACTGCAAAAATGAATGGTACCATAACTGTGAAATAAAAATGAACYATAACTTTAATGTACTTAACATTTATGTAGAATTTTATCTACCTGTTTGTGGTTGTCAGCAGTCTTACCTGAACCAATTCTCTGTATGCAGATTTAGCAA Celera SNP ID: hCV7538686Public SNP ID: rs1473247 SNP Chromosome Position: 158536149 SNP inGenomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 72729 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 93|C, 27) SNPType: INTRON Context (SEQ ID NO: 112):ATATCTTTACTTCATTTCCTTTATCCAATCCTCCATTGATGGAGACAGTCAGGTTAACTCCATGTCTTTGCTATTGTGCATAGTGCTCTGATAAGCATATYAGTGCAAATATCTTTTTTTATATAATTGTTTCTTTCCCTTTGGGTTTATACCCAGTAGCAGGATTGCTGGATCAAATGGTAGTCCTATTTTTAGTTCTTT Celera SNP ID: hCV1030180 PublicSNP ID: rs270659 SNP Chromosome Position: 158493420 SNP in GenomicSequence: SEQ ID NO: 15 SNP Position Genomic: 30000 SNP Source: dbSNP;Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T, 97|C,21) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 113):CATCCTGGGCCACACGCAGCCCAGGAGTTGGACAAGCTTAGTCTACAATTTCAAAGAAGTAACTTGCTGAGGTAACATATTTACTAGGTAAGGAAACAATYTGTATCAAGTCTGATTCTAAAGTTAATTTTCCTTTCTACTAACCATGCTGCCTACCTAAGTGGAATGAACTAGATTGTGAAAACATGGATTCAAGTTAAA Celera SNP ID: hCV2081970Public SNP ID: rs1897565 SNP Chromosome Position: 158550843 SNP inGenomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 87423 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (T, 93|C, 27) SNP Type: INTRON Context (SEQ ID NO: 114):GGTTACTAACAGCACTGAACATTATCAATAAGTATATGAAAACATTTGCAATTATTTGGTGAAATGTTCACATTCTTTGCCCATTTTTCTGCTAGAATACRTATCCTACTGCCTGATCGAAATAGTAATCCTTAGTCACATGATTGCATTTTTCTAATATGTCCCTTGTCTTAATATTTTAAATAACTTTATTCTCTTATA Celera SNP ID: hCV2081982Public SNP ID: rs10076782 SNP Chromosome Position: 158537541 SNP inGenomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 74121 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 93|A, 27)SNP Type: INTRON Context (SEQ ID NO: 115):GAATGTATGTGACATGATATTTGCATTTAGCCCTTTCCAAATATTCCATAATTATAAAATGCTTTGTATGAATAAGCTTTTACATTATGACATCCTTGTAYAAACTACTTGGAACACATTTCCTAATATTCTCTTAGGCTAGGAATTACTGAATCAGAAAAAAACATTTTTAAAGACTTTGACACACTGTCAAGACTGCCC Celera SNP ID: hCV2081983Public SNP ID: rs17663721 SNP Chromosome Position: 158537218 SNP inGenomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 73798 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 96|C, 24)SNP Type: INTRON Context (SEQ ID NO: 116):ATTTATGAAGATTTTCCCTTTAACAATTATTTCATTAATAGAAAAGTTGTTTCATGAACTATTAGTATCATCTCTTAATTGTCCTCTAACTTGAGAATTASGACGCTTTTCCTTTCCTTTTTTAATTCCCAGTACACTGAATTGAATTCATCACAATCCTTGATTGACGATGTACTGTCATCATTTGTCTGTGCATGTCCC Celera SNP ID: hCV2081991 PublicSNP ID: rs13178603 SNP Chromosome Position: 158524593 SNP in GenomicSequence: SEQ ID NO: 15 SNP Position Genomic: 61173 SNP Source: dbSNP;Celera; HapMap Population(Allele, Count): Caucasian (G, 96|C, 24) SNPType: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO:117): GCTTTCTACCAACAGATGTGCAGGGTATTTTTCCCTCTGCCCTTGTTTGTTCATTAATCCATGGTAGGGGACACCAATGGATGGTCACAGTTATGATTCCYCCCATCAATGTGTTTTGCTTGGTTTTCATAGCATTTTTAATTATTTATTTTTGGAGACAGAGTCTCATTCTGTCACCCAGGCTGGAGTACAGTGGCGTGA Celera SNP ID: hCV3220380 PublicSNP ID: rs270654 SNP Chromosome Position: 158497687 SNP in GenomicSequence: SEQ ID NO: 15 SNP Position Genomic: 34267 SNP Source: dbSNP;HapMap Population(Allele, Count): Caucasian (T, 109|C, 11) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 118):AGCTTGAAGAGACTAAGAGCAGGCAATCCAAGTCTCCTCCACATGTGGAAACCAAGTCCAGAGACGGAGCAGTAACTGCCCGGCTCCCACGGCTTGTAATYGCAGAAACAAGCTTTAAGCCGGCTGCCTCCTTCCTCGTTGCTTTTACCATTATTTAATTTGTAGGCTTCACAAAGGCTATATGTGTTGAAATTGGCTAAA Celera SNP ID: hCV3220386Public SNP ID: rs270661 SNP Chromosome Position: 158492732 SNP inGenomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 29312 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (C, 95|T, 25) SNP Type: INTERGENIC; UNKNOWN Context (SEQ IDNO: 119): AGTAGGACTATAATCAGAAGGAAAAAGCAGGATTTGACTTATAGGTATTCAATTCTTTATTATTTTTGTCTTCATTACAATAGCTAACACATATGGAACAYTGTCTGCCTGGTACTAAACTCATTTAAATCTCACAGAACTCTATGAGGAAAGCACAGCTTTCATTATTAGCTCCGTTTTACAGAAAGTAACGCAATTATC Celera SNP ID: hCV11270803Public SNP ID: rs13158488 SNP Chromosome Position: 158535849 SNP inGenomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 72429 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 96|C, 24)SNP Type: INTRON Context (SEQ ID NO: 120):ATAAAAAGACACACAGTCCTCTCCTTCCCTTTCAGACTAGTTTCCTCTTTACTGCAGACTGCGACGCAAGGCCATCCACTAATCTTTGATGCCTGCTCACYGCACAGGCCCCTTCCTCTCTCCCCGCACCTCCTCCCACAACGCCTGCAGATCTCAGATGCGTTTGAACTACAGTAACCCCAACCCAGCTCGCGGCAAGCA Celera SNP ID: hCV27841092Public SNP ID: rs6556405 SNP Chromosome Position: 158567680 SNP inGenomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 104260 SNP Source:Applera Population(Allele, Count): Caucasian (C, 13|T, 25) AfricanAmerican (C, 17|T, 11) total (C, 30|T, 36) SNP Type: UTR5; INTRON SNPSource: dbSNP; Applera Population(Allele, Count): Caucasian (T, 89|C,27) SNP Type: UTR5; INTRON Context (SEQ ID NO: 121):GCCAAAAATACTATTGACACAAACATGCATCACAACTCACTCTACAGCATTAACCAAACAATCCATAACAAACTAAGTTGACAATGGCAAAGCTGTTAGTKTTTAAATTATACACAGTAATTTGTAATTAAAAAGCAAGACCAGTGGCATTTAAAAATGATGACCTAGGCCAGGTGTAGTAGTGCACACCTATAATCCCAG Celera SNP ID: hCV30377542Public SNP ID: rs6888950 SNP Chromosome Position: 158557329 SNP inGenomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 93909 SNP Source:dbSNP Population(Allele, Count): Caucasian (T, 90|G, 24) SNP Type:INTRON Gene Number: 4 Gene Symbol: UBLCP1-134510 Gene Name:ubiquitin-like domain containing CTD phosphatase 1 Chromosome: 5 OMIMNUMBER: OMIM Information: Genomic Sequence (SEQ ID NO: 16): SNPInformation Context (SEQ ID NO: 122):GTCCACCCCCTGACAATGATGATGTTGTTAATGACTTTGATATTGAAGATGAAGTAGTTGAAGTAGAAAATAGGTAAGTGCTTTTCGCTTTAGAAGTAATSAGTTGTCATGTGAGAACAAGTGAATATTTTATCTAATTATATGTTTTCCATTAGGGAAGAAAACCTACTGAAAATTTCTCGCAGAGTGAAAGAGTACAAA Celera SNP ID: hCV2084255Public SNP ID: rs3734104 SNP Chromosome Position: 158630059 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 62850 SNP Source:Applera Population(Allele, Count): Caucasian (C, 10|G, 22) AfricanAmerican (C, 25|G, 11) total (C, 35|G, 33) SNP Type: INTRON; PSEUDOGENESNP Source: Applera Population(Allele, Count): Caucasian (C, 14|G, 18)African American (C, 25|G, 7) total (C, 39|G, 25) SNP Type: INTRON;PSEUDOGENE SNP Source: dbSNP; Celera; HapMap; HGBASE Population(Allele,Count): Caucasian (G, 53|C, 67) SNP Type: INTRON; PSEUDOGENE Context(SEQ ID NO: 123):GGAAAGTTTTCGGAGTTTTACAGCAAGAAAAACACCATTATGTTTGATGACATAGGGAGAAATTTTCTAATGAACCCACAGAATGGACTAAAGGTAAGACRTACTTTTACTTGTTATGTGCTCATGTAATCTGGGCTGTGTGGTAGAACTTTTGTAGTAAGCACTGTTGAATTTCATATATTTTTGGAAGTACTGTATTCT Celera SNP ID: hCV25633374Public SNP ID: rs12520035 SNP Chromosome Position: 158637948 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 70739 SNP Source:Applera Population(Allele, Count): Caucasian (A, 35|G, 5) AfricanAmerican (A, 29|G, 3) total (A, 64|G, 8) SNP Type: INTRON SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 112|G, 8) SNPType: INTRON Context (SEQ ID NO: 124):TTGGATCTAAATCACAAATATTGGGAAAGGTAAGTTTTAATTGCTTATTTATTTTCTCTTTACATCAATGAAGAAAAAATTATCATTTTTCATCAGTGACYCCAGTATATATATAGCTGTCTTAATTTTTATTTAAAATAGGTGACTTCTAAAAACATTTTCTAATCCAGTGACCTACCCCCAAAAGTATTTTCCCCTTTC Celera SNP ID: hCV7537829Public SNP ID: rs1433046 SNP Chromosome Position: 158642997 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 75788 SNP Source:Applera Population(Allele, Count): Caucasian (C, 10|T, 24) AfricanAmerican (C, 17|T, 5) total (C, 27|T, 29) SNP Type: INTRON; PSEUDOGENESNP Source: dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian(C, 53|T, 67) SNP Type: INTRON; PSEUDOGENE Context (SEQ ID NO: 125):GAGAAGTATGTAAACAGCTAACTATATTTTGTTAAAGATTTATAGGAACATTTTCACATGACAAAGAAGTTCCCAACCACTGTGGACCCTCACTGGTGCCSAGATGTCTGTGGTTATTGGTCATCTCTTGATCTCAACTCCCTCCTTGTCCCCTTACCCTTACACAAAAAGAGCCTAAAATTTGTCTTGACTTAAGATGGT Celera SNP ID: hCV1030157 PublicSNP ID: rs254837 SNP Chromosome Position: 158615778 SNP in GenomicSequence: SEQ ID NO: 16 SNP Position Genomic: 48569 SNP Source: dbSNP;HGBASE Population(Allele, Count): Caucasian (G, 7|C, 99) SNP Type:INTRON Context (SEQ ID NO: 126):TGTAACCACATTTTGGATTATTTCAAGGTCCAATGTGATACAAAAGTTGGAGAAATTGAAAATAAATTTTATAAAAATTATAATGAAGAAATATACAGCAWAGAAGAATAAAAGGGAAACAATAAAGGGTTAAAAGTACAGATTCCAGAGCTGTCCAGTTCAGCAGCCACTAGCCACATGTGGCTATTGAGCATTTGAAAT Celera SNP ID: hCV1030159Public SNP ID: rs254839 SNP Chromosome Position: 158607721 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 40512 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 94|A, 24) SNPType: INTRON Context (SEQ ID NO: 127):ACAACTTGAAAACAGAAGCAATGCACCTTCAGAATTGATCCTGCCTCCCAAGAAGCCTACTTCCAAAGATCAGAATCATAAAATGCATTTTTGCTGTCTTYGTAAGCAATTTTGATATTTTGTCAGTTTCATTGCTATTAAGTGATCATTCCTTGCTTCAAATGAAAGCTAGAGAGAATTACAATTCTTATGATACTGTTT Celera SNP ID: hCV1030161Public SNP ID: rs254843 SNP Chromosome Position: 158605897 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 38688 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 95|T, 25)SNP Type: INTRON Context (SEQ ID NO: 128):CTTCCCGAGGTATGGAAGGATTGTGAATCTACTCAGTCAATCTTAAAAGGGGCAATGGGGAGAGGGAAAACAAGGAACCCTCACAGGCTAATTTTTAAACYACATCTCTTAAGAAAATATGGAGAAGCAAAGAGAGGAAAATGTAAATTACCTGAAATTCTACCACTGTAAATATGTTGATATACTTTCAGACTTTTTCCT Celera SNP ID: hCV1030169Public SNP ID: rs254850 SNP Chromosome Position: 158599309 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 32100 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (C,95|T, 25) SNP Type: INTRON Context (SEQ ID NO: 129):CCTCCAGAGTTATATACAAATTGTAATCATTCATTGATATGTATTGTTACAAGCGTAATATGTACAGCTGGCCCTCTGGATCCACAGGTTCCAAAACTACRGATTCAACCAACCTCGGGTTTGAAGTATTAGGGGAAAAACCCAAAGATAATAAGACAACAATAAAAAATAATGGAAGTAAAAGCAATACAGTATACCAAC Celera SNP ID: hCV2081927Public SNP ID: rs194228 SNP Chromosome Position: 158619371 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 52162 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,67|A, 53) SNP Type: INTRON Context (SEQ ID NO: 130):TAAATAAAATATCACATCTATTATATTTACATGCATTAATAATAGCTTATTGGGAATATTATTATGGGAAAGTCATGAGGATAAAAAAGTTATAGTTTAGWTTCACCATGTTTAAAATCATAATAATACGGCTGGGCGTGGTGGCTCATGCTTGTAATCCCAGAACTTTGGGAAGGCCAAGGCGGGTGGATCACGAGGTCA Celera SNP ID: hCV2081932Public SNP ID: rs4921200 SNP Chromosome Position: 158610802 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 43593 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T,25|A, 95) SNP Type: INTRON Context (SEQ ID NO: 131):CTGGGATTACAGGCATGAGCCACCACGCCCAGCCAAGTAGGCCATCTTTTGATCCATGTTTCAGCTAACCAAGCAAATAAATTATTAGAACCTTTTTTTAWCTCCCTGATCTGCAACATTAAATGCAGAATCCCTGCTTAGTGGGTCCATATCAGTAAATTCAGCCTGATCCAACTTTATGTTCTTTCCACCATTATCCCA Celera SNP ID: hCV2081943Public SNP ID: rs254852 SNP Chromosome Position: 158596372 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 29163 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 95|A, 25)SNP Type: UTR5; INTRON Context (SEQ ID NO: 132):AGGTGAGGAGGACTGACCTTGTTAAAACACAGATTCCTAGGTCCCTTCTCTCCACCCCAATTACATTTCTACCAAATTACCAAGTGAGGTCAATGCTGTTSGTTAGCCCAGGGACCATGCTTTGAAAACCACTAGTCTAGAAGAGCAATCACTTGTCCAGGGTCACCTGGAACTCAGATGATTTCACTCCAAACTCTGCAC Celera SNP ID: hCV2084251Public SNP ID: rs10515780 SNP Chromosome Position: 158624371 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 57162 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 25|G, 93)SNP Type: INTRON Context (SEQ ID NO: 133):CTTGTTAAAACACAGATTCCTAGGTCCCTTCTCTCCACCCCAATTACATTTCTACCAAATTACCAAGTGAGGTCAATGCTGTTCGTTAGCCCAGGGACCAYGCTTTGAAAACCACTAGTCTAGAAGAGCAATCACTTGTCCAGGGTCACCTGGAACTCAGATGATTTCACTCCAAACTCTGCACTACTACGCATCACAATA Celera SNP ID: hCV2084252Public SNP ID: rs10866711 SNP Chromosome Position: 158624388 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 57179 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 25|C, 93)SNP Type: INTRON Context (SEQ ID NO: 134):ATTTGTCCATTTGAAGATATTATGATTTATACTACACTGTTGTATTATAGTTTTAATTGTGGTAAAATTGTCAGTCTAGCAATCAATGAAAAATAAAACCNGCACCGTGAATGTGTTATTAACTGTATAAGTATAGTAGTAGCACAAATGATCAAATTTAATATGGTAAATCTGCCCAGGAAACATACATAACGAATTATT Celera SNP ID: hCV2084254Public SNP ID: rs2420825 SNP Chromosome Position: 158629709 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 62500 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): no_pop (C,—|T, —) SNP Type: INTRON; INTERGENIC; UNKNOWN Context (SEQ ID NO: 135):ATAAGGGACTGTAGCTCGTCATTTGATGTAGTAGGATATGTAATGATTTAGAAATTTTCATGACACATTTAAGTGAAAGAAGTATTTTAGAGAACACTGTYGTAAGCCGTTAGAAAATAGTTCTTAACCTTTGTTTGGTTCAGGATTACCCTTAATTTAACAAAGAACCTGTCAACTCTCTGAGGCTGCTCTTGTTTATAA Celera SNP ID: hCV2084259Public SNP ID: rs7708700 SNP Chromosome Position: 158636313 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 69104 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (T,26|C, 94) SNP Type: INTRON Context (SEQ ID NO: 136):GCCTAGGCTGGTCTCGAGGTCCTGCACTCAAGCGATCCACCTATCTCGGCCTCTCAAAGTGCAGGATTACAGGCATGAGCCACTGCGCCCAGCCCAGAAAKAGTTCTAAAATGGAGAAATATCCTCAAATGCTGTGTTTTGTTATCATGCTTTCATAATGCACTTGGTAGAAATCTCAAAGATTTCATGTAGATCTTAAAA Celera SNP ID: hCV2084262Public SNP ID: rs17665189 SNP Chromosome Position: 158640194 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 72985 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 53|T, 67)SNP Type: INTRON Context (SEQ ID NO: 137):ATCATATTATCTAAAATTAATTTAAAATTATTGAAAGACTATCTTGAGTTGTATAAAGATATTTGAGCAGGTGTCTTTTACAAAACAGCAGAATTCTTTAYTGAAGCTATAAAATAAGGAAAAGTGCATAAATTTATAGTTCAACAAACTGTAAAGATAATTCTTGTAAAAAATTTTATTCCACTAAAATTACTCATGATT Celera SNP ID: hCV2084263Public SNP ID: rs10515782 SNP Chromosome Position: 158641855 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 74646 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (C, 26|T, 94) SNPType: INTRON; PSEUDOGENE Context (SEQ ID NO: 138):TAAACTCTTTTTCATCATAAAATAGATCAGCCTTAAACATTTGGAAAATATGGCAGTTCTTTTTATGGAAAACTCTTGCATAATTAAAAATGATTTTAACRGAGAATTTAATGATAAAGAAAAATGCTTATGATAAAATGTAGGAGGAAACAGGTTATATAAATGTATAATGATATCTCAGCTATATAAAAATTTAATAGA Celera SNP ID: hCV2084265Public SNP ID: rs7736656 SNP Chromosome Position: 158642268 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 75059 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (A, 26|G, 94)SNP Type: INTRON; PSEUDOGENE Context (SEQ ID NO: 139):TGGAATATAATCCCTCTTCTCATACTGTAACTTAATGTCAGGATAAGATAAAACACATGTAAAAATTTCATAAATAGTATTAAAAATTACCAGTAACTTGWGTGTAGCAGAGAAATTAGAAAAGTTTATCCTACTAAAAAAACAATTACTCATAATTTTCCTTTTTAAAGATAACCACTGTTACCATCTTGGTATATAGTC Celera SNP ID: hCV2084266Public SNP ID: rs10042630 SNP Chromosome Position: 158643346 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 76137 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (A, 26|T, 94)SNP Type: INTRON Context (SEQ ID NO: 140):CAAAGGCCCCCTTCCATTTCTCCTCTCCAGAGTGTTCCAGTAAGAACATCCCCTTCTAGCTATTTCACACATGGACAACCAAGAAATAGTCATTTACAGARCATTTTGCATTTGTACAATTTCACTCGTTATTTCTCCCCCAGTACCTAATGGGGGCTGCAGCGTGTACTCTGTTCGTGGTTAAATTCTGCTGCCAGAAGT Celera SNP ID: hCV2084270Public SNP ID: rs2082412 SNP Chromosome Position: 158650367 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 83158 SNP Source:dbSNP; Celera; HGBASE Population(Allele, Count): Caucasian (G, 93|A, 27)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 141):TCCCATGATGGTCAAGGAATAATTTTGGAGGAGACGTTTAACTTTAAAAAAAAAAATACAATCATTAGTTTCATGTTTGTTTAAAAGAAACTTTGTTTTCSTAACCAACATTTGAGCTCCATTCATCTCTTGATGCAGGGAGAGATGTTATTGTAAATGTCTAGTTCTTTATGTTACTTTACAGTAGGGTTTTTAAAAGAC Celera SNP ID: hCV7537756Public SNP ID: rs1368437 SNP Chromosome Position: 158639557 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 72348 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (C, 112|G, 8) SNP Type: INTRON; PSEUDOGENE Context (SEQ ID NO:142): ATAAAAAGACACACAGTCCTCTCCTTCCCTTTCAGACTAGTTTCCTCTTTACTGCAGACTGCGACGCAAGGCCATCCACTAATCTTTGATGCCTGCTCACYGCACAGGCCCCTTCCTCTCTCCCCGCACCTCCTCCCACAACGCCTGCAGATCTCAGATGCGTTTGAACTACAGTAACCCCAACCCAGCTCGCGGCAAGCA Celera SNP ID: hCV27841092Public SNP ID: rs6556405 SNP Chromosome Position: 158567680 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 471 SNP Source:Applera Population(Allele, Count): Caucasian (C, 13|T, 25) AfricanAmerican (C, 17|T, 11) total (C, 30|T, 36) SNP Type: UTR5; INTRON SNPSource: dbSNP; Applera Population(Allele, Count): Caucasian (T, 89|C,27) SNP Type: UTR5; INTRON Context (SEQ ID NO: 143):AGGGAATTGTGGGGTCAGAGCCCCCATACAGAGTCCCTACTGGGGCACTGCCTAGTGGAGCTGAGAGAAGAGGGCCACCACCCTCCAGGCCCCAGAATGGSAGATCTGACAACAGCTTGTACTGTGTGCCTGGAAAATCCACAGACACTCAATGCCAGCCCGTGAAAGCAGCTGGGAGGGAGGGTTTACCTTGCAAAGCCA Celera SNP ID: hCV27883435Public SNP ID: rs4921442 SNP Chromosome Position: 158626678 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 59469 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (C, 88|G, 26) SNPType: INTRON Context (SEQ ID NO: 144):ATTCCCAAAGTGTTACTTTTACTGCTATACTTTAAAATTTCTTCATTTGCCACTTTTTAGGTTTGTGGTCCCGGGCAAGTTTAATTTCTTTTCAGGATTCYCATTTGTATAATGAGGACAACAGCTGTTGGTTCAGGATTGTGAAGCTTCAATGAGATAATTGTTTAGCATGTTTTTATTCCATCATGAACACCATTTGTA Celera SNP ID: hCV27936085Public SNP ID: rs4921437 SNP Chromosome Position: 158623529 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 56320 SNP Source:dbSNP; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (T,26|C, 94) SNP Type: INTRON Context (SEQ ID NO: 145):GGATTACACAAATGTGTGAACAGCAGAAGGTAGAAACATTGAGGGTTATGGTACAGTCTGTTTGCCACAATCCCTGAATCCATTCTTTAAAAAGTTGGTAKAAAAATACCTACTTTAGAGGGTTGTTATGTGAATTCAAAACAAGATAACATATATCGAGTGTTTACGTGGTACCTGGCACATAGTGAGCATTCAATAAAT Celera SNP ID: hCV30557642Public SNP ID: rs10056599 SNP Chromosome Position: 158655488 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 88279 SNP Source:dbSNP; HapMap; ABI_Val Population(Allele, Count): Caucasian (T, 93|G,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 146):CCGATAGTGCCCACGGTGAACCCGTATTATTGTTCCTCTATCAGGTAGCTCAATATATATGAAAAGATAGTGGAATCTGCTAGGTGATACAGGTGAGGGARGATCCTTTGATTTGAGTTGATGACAGGAATTCAGCTGAGTCATGTTTTAGGATGCAGGCTCATACCTAGAACCATCTTGAAAGTACCATCTGGGAGCAAG Celera SNP ID: hCV31985608Public SNP ID: rs12652431 SNP Chromosome Position: 158654672 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 87463 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 94|G, 10) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 147):GACTTTTCAGGAATCTAGAGGTAAATCAATTATTTAATTGAATACAAATCCCTCTTACTTTTATTCCCAGTTCTTAATTCTCTGGAGCACTGATTGCTATYACTTCTTGTTGGATAATCTGTGAGGAGAACTGCTGTAGCTTCCTAAATAAGGCTTTTGAAAGAGCCAGTGGTTTGTCAGAAAAACATGTGACTAAAATCC Celera SNP ID: hCV30629526Public SNP ID: rs4921458 SNP Chromosome Position: 158648241 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 81032 SNP Source:dbSNP; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (T,26|C, 94) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 148):TAAATTGAAACATTATGTGGCCTTTCGTGTGGGTTCTTTAACTTAGGATAGTGTTTTCAAGTTTCATCCATATTGTAGCAAGTATCAGCACTTCATTCCAYTTTATGGCTGGATGACATTCCAATGTATGGGTCTGCCATATTTTGTTCATGCCATTTATCCACTCATGGATATGTAGCTTGTTTCCACTTTCTGCCCATT Celera SNP ID: hDV70267720Public SNP ID: rs7719425 SNP Chromosome Position: 158603516 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 36307 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 96|C, 24) SNPType: INTRON Context (SEQ ID NO: 149):TCTGGAGCCAGGAGTTAGAATCCCTGAGTTCATCGTTTTCTTTCATCACTTTGTCCAGCAAACTTAGGAGCAACCAAACAACTTTATGACATTCCTTGATYCTCCACATATGGTCAAAGGTATTATGTATAGAGTCACTAAACTCCTTGCCTCTGCAGAGCAGTGAATCAGGAGTATCAAATGCATTTATTTTGCATAACT Celera SNP ID: hCV30431544Public SNP ID: rs7715173 SNP Chromosome Position: 158597209 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 30000 SNP Source:dbSNP Population(Allele, Count): Caucasian (T, 96|C, 24) SNP Type:INTRON Context (SEQ ID NO: 150):GTTTACAATGAGGATATTTTAGGGAAAGAATACTAATCTAGGTAGTGAATTGCCATAAGTATAAAAACTGTTGACTTGGAAGAAAAGTGGTTATGTTGTCYTTAATGGTTTCTGTTTAAGGCTTGGAGAGAAGTGCTTTTCTTAATATGTACTGCACCAGGTAAAGGTACAAAAATGTATTCTTGAGTCTTGAGAAGAAAT Celera SNP ID: hCV2084260Public SNP ID: rs13153734 SNP Chromosome Position: 158639291 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 72082 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; CeleraPopulation(Allele, Count): Caucasian (C, 98|T, 20) SNP Type: INTRON;PSEUDOGENE Context (SEQ ID NO: 151):CGAAATCAGTTATTGGACTAATGATACCTATAGCAGCTCTTCAGTGTAAAAGGTAAGGAATGGAAAAACAGGTTGTTACAGTAAGCAACTGAAACTTATTYTTTATTCATGGAAAGTAAAATAGTTCCTTGAGAGGAAGAGGAACTACAGGATAGGGACTGGGAAAAAAGGATATGCAAAAAAACGCAGATTAGTTGCATT Celera SNP ID: hCV2084269Public SNP ID: rs6895626 SNP Chromosome Position: 158646681 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 79472 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 26|C, 94)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 152):TCTGGCGAATTCTACGTGAAATGTCAGGAACCAGTGAAGGGTGTTAAGCATAGAATGACAATCTAATTTTTTTTAACAGCCTTATTGAGATAGAATTTACMTATCACAAATTTACCCATTTGAAGTGTGCAGTTCAATGGTTTTTAGTGTATTTAGAGAGCTGTACAACCATCACTGTAAGCTAATTTTAGAACCTGATTT Celera SNP ID: hCV31985611Public SNP ID: rs13161132 SNP Chromosome Position: 158649646 SNP inGenomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 82437 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (A, 88|C, 16) SNP Type: INTERGENIC;UNKNOWN Gene Number: 5 Gene Symbol: hCG1979566 Gene Name: Chromosome: 5OMIM NUMBER: OMIM Information: Genomic Sequence (SEQ ID NO: 17): SNPInformation Context (SEQ ID NO: 153):CTGTGTGCCCAGCACTTCCTCTGCATGCCTCAGATGCATTTGACAATCTCAGGTGAACTGCACTTCAGGGTCAAGGGAACCCCGGCCATGGTTCTAAGAARCAACTCCCATTTTAGTATCACCTACATTTGAAACCACAGAGCACTGTCCAGGAGAGGTGATGGTGGTGGGTCTCCTCCTTTGGCTCTCTGGCCCATCAGC Celera SNP ID: hCV1992693Public SNP ID: rs1433048 SNP Chromosome Position: 158688423 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 27905 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (G, 21|A, 99) SNP Type: INTRON Context (SEQ ID NO: 154):TGGACAGATGAAGGCTGGTACTCATGCTTCTTCCCACTGCAAGAAGAGGAGCCATGTGTCATTTCCTCTCTGTGACTGTGAGCAGCCCTTGGCCCCTGGARCTCCCCAGGTACAACCGGAACAACATCATGGTGCACTGGGCTTACTTTTAAGCCTAGAACATGAAGAGAGCTGGTTAGAAGGGGACAAGCAAAGGACTGG Celera SNP ID: hCV1994960Public SNP ID: rs4921483 SNP Chromosome Position: 158700943 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 40425 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,19|G, 99) SNP Type: INTRON Context (SEQ ID NO: 155):TCAAAGCAGAACCTTAGGCTCTAAGGGAAACAAGACAGAAGGATTCTGCTGACAAGACAGTAAAGTAGCCTGCTCATCTGGTGGTAGGCACTGTGTCAGCRTTCTAGGTTGTAAATGTAGGAAGTAAGCAGATCAGAGGTTTGCTCAACAACCTGCCTAGTGAGCCAAACTGCTTGCTCTTGAGGCCATGTAGTCCTTCTG Celera SNP ID: hCV1994965Public SNP ID: rs953861 SNP Chromosome Position: 158705160 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 44642 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (G,20|A, 100) SNP Type: INTRON Context (SEQ ID NO: 156):CCTGACCTTGTGATCCTCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGGCACCGCGCCAGGCCTATTGTCTCTTTAATACCTCTCTATCAYTTGTTGATCTCTCTTCTTAAGGAGGGCAAGCACTCTTCAGCCTTAGAGGCATTAGCAGGCAACAGCATCTATTCTAGTGGATCTCATCCTTGGCTGCATG Celera SNP ID: hCV1994966Public SNP ID: rs11746138 SNP Chromosome Position: 158706357 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 45839 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 108|T,12) SNP Type: INTRON Context (SEQ ID NO: 157):TCCTGTCTTCTTTAGGCCCAGTTTCCTCAACAATGAAATGGGACTAATTATCCCAGGTCACACTTCTCTCTGGGCTTACCCTGGGAATCAGATGATTGAGSTTTGGTAAGTATTATTTGATAAACAAGTATGAGGAAGGAAATAAAAGGGAGATCAGTGCTGCAGAGATGGCTAATTGGCAGATTTACACAGAACTGGATT Celera SNP ID: hCV1994967Public SNP ID: rs11747112 SNP Chromosome Position: 158707187 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 46669 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 108|G,12) SNP Type: PSEUDOGENE Context (SEQ ID NO: 158):CTTCTTTATTTTCTCAACAATGTTTTGCAGTTCTCAGCATATAACTTTCATTTCTTTTGTTCAATTTATTCCTAAGTATTTAATACTTTTTGGTGCTATTKCAGATGAATTTTCCTATTAATTTTCATATTGGTCATTGCAATTGTATAAAAATACAATTATTTTTGTATATTGATCTTGTTTCATGCAATCTTGCTGTGA Celera SNP ID: hCV1994971Public SNP ID: rs7725339 SNP Chromosome Position: 158709579 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 49061 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 73|T, 35)SNP Type: INTRON Context (SEQ ID NO: 159):ATGAGGTGCCCTGTGGGGTTAAACAGAAATGAGAGATGCAAAGAGTGTAAGGTGGCATTTCCATTTCTGGTCTCTGAGCTCTACCTTTATGCACTGTTTTRGCTGTTCAGTCTTTATCTAAATAACTTCTAATAACTCCACTGCCACCGCCATCTAGCTATGCTCTTGGGTAATTTGAGTTGAATTTTTGTCACATGCAAC Celera SNP ID: hCV1994973Public SNP ID: rs1157509 SNP Chromosome Position: 158718688 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 58170 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,20|G, 100) SNP Type: INTRON Context (SEQ ID NO: 160):GGGGTTAAACAGAAATGAGAGATGCAAAGAGTGTAAGGTGGCATTTCCATTTCTGGTCTCTGAGCTCTACCTTTATGCACTGTTTTAGCTGTTCAGTCTTYATCTAAATAACTTCTAATAACTCCACTGCCACCGCCATCTAGCTATGCTCTTGGGTAATTTGAGTTGAATTTTTGTCACATGCAACTGAGAGTCCTGACT Celera SNP ID: hCV1994974Public SNP ID: rs1157510 SNP Chromosome Position: 158718702 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 58184 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T,20|C, 100) SNP Type: INTRON Context (SEQ ID NO: 161):GAACAGATGACCAGGGGTGACTCAGGACAGAGCAGGTGACCAGGGGAACAGATGTGAACTGCTGATTAGAACTGGTGGAAAAAGTTGTTTACTGAAACTAYGGGCGAGGAGAATGAGGAAGTTAAACTTTAAAATGGAGAACAAAGAACTGAACATACTGACATACTGATTCTTTGAAGAGAAATTTAGAACTCACTGTAT Celera SNP ID: hCV2084277Public SNP ID: rs6874870 SNP Chromosome Position: 158662099 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 1581 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (T, 23|C, 93) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 162):CCACTTCCAACATTGGGGATCAAATTTCAACATGAGATTTGGAGGGACAAATATGCAAACCATATCAGGTGTTGATGGTGAAGGGGTGCTGTGTTTCTTTYTGGGGTATTGAAAATATTCCAGAATTTATTGTGGTGATGGGAGCACAACTCTGTAAGTGTATAAAACCTGTTGAATTAGACACCTTAAAAGAGTCACTTG Celera SNP ID: hCV2084281Public SNP ID: rs7730390 SNP Chromosome Position: 158663370 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 2852 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (T, 91|C, 27)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 163):GTGATAATGTCTGGGCTTGGCAATTACCTTCAGTCTGTTCTCCTCCTGTGATACAGTTAATTTTTCCTAATTAATGAGATTCCTGGGGAGGAAACTCATGRCAATTGAGTGCCTTTTTGGAAGATCTATCTTTAGGCAGACGAGGCAAGTTCAGAGACCACCCTTCCCTGTGCTTTTGAAACAGGGGTGAGAGACAGCAGG Celera SNP ID: hCV2084283Public SNP ID: rs1549922 SNP Chromosome Position: 158664126 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 3608 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (G, 63|A, 53) SNP Type: INTERGENIC; UNKNOWN Context (SEQ IDNO: 164): ACCAAGGCCAGGTAAAAACCACCCCTTCATCCCCTAAACCTTGCAAGAAGCACAGGGTCCAGAATTATGCTTCTTTCAGGTTCTAAATAGCACAATAAAAYTAATAACAATAAGCTTTTAGTTATTAGATCAGGTACATTTTACTTTACAGTAAGCTTTTACTTATTGGATCAGGTACATTTTAAAGCAATTTTTGAACAT Celera SNP ID: hCV2084288Public SNP ID: rs6870828 SNP Chromosome Position: 158671090 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 10572 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 54|T, 64)SNP Type: INTRON Context (SEQ ID NO: 165):AATTACTTAAATATTTAAATAGCATGAAGGCCCATGGCAACTTGAGAGCTGGAAAATCTATACATAAATTAGCTGATTGTTTCAATGAGCATTTAGCATCKAACTATACAAATACAGCAAAGATATCATTGTGATCCTAAAAAAACGTTTTAAAGCAAATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTT Celera SNP ID: hCV2084293Public SNP ID: rs3212227 SNP Chromosome Position: 158675528 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 15010 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T,93|G, 27) SNP Type: UTR3; INTRON Context (SEQ ID NO: 166):ATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTTTAAACATTTTGCTTAATATCTTCCACTTTTCCTCCAAATTTTCATCCTGGATCAGAAYCTGGAAGAGAATGCCAAAAGTTGATGTGGGGTGACATTGTAACAGCAATGTCTCTTCTTATTTCTCACAACATATGATCCTGGGCAACTGGGTTTCAGGG Celera SNP ID: hCV2084294Public SNP ID: rs3213120 SNP Chromosome Position: 158675686 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 15168 SNP Source:dbSNP; Celera; HapMap; HGBASE; Population(Allele, Count): Caucasian (C,117|T, 3) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ ID NO: 167):GGAAAATGTCTTAGGTTCTCTGTGTCTGTTTCCTCACTTATAAATAGGGATAACAATAATGCCTACTTCATAGAATTATAGTTCAAGGTAAAAATCACGTYAAACTCTTAGCAAGTCTTTAGCACATAGGAAGCACTCAATATCACCTATTAGTCATACAGATCTTAAATAGGGAAAGTACTTGCCAAGATGTAAAATAAT Celera SNP ID: hCV2084295Public SNP ID: rs2195940 SNP Chromosome Position: 158676930 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 16412 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (C,110|T, 10) SNP Type: INTRON Context (SEQ ID NO: 168):GGCTTTGTCCAGTGATTTTAAAAGTGGGGTGAAAGGAGTCTGGGGCGGTACAAAAGGGCCTCTGGAACCTTGCAACAGGCAAAGGAATTCTGCTGTAAGGYGAGGAAGCTGGGAAGCCAATATCTTAGCCTCTATAAGTGTAGACATTCTGTTTAGTAAAATAATTTTATAATATCTGGAACAGCCAGGAGCTATCCATTT Celera SNP ID: hCV2084296Public SNP ID: rs2853696 SNP Chromosome Position: 158677238 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 16720 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (T, 26|C, 94) SNP Type: INTRON Context (SEQ ID NO: 169):CCCCTCTGACTCTCTCTGCAGAGAGTGTAGCAGCTCCGCACGTCACCCCTTGGGGGTCAGAAGAGCTGAAGTCAAAGACAGAAATTAGCCTGTGTTACACMTTGGGGAGAGAGTTCCTAGTGATTGTAGCCAGTAAGGCAGGTAAGGCCTCAACTGTTGTCTGAGGACACAGTTTCTCCAACTGGGCTGATTTCTACCCAG Celera SNP ID: hCV2084297Public SNP ID: rs919766 SNP Chromosome Position: 158680142 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 19624 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,110|C, 10) SNP Type: INTRON Context (SEQ ID NO: 170):GTCTGCTTCAGGGCCCCTAAGATCTACGCCCTGGAGCTCTTGTTTTTATTTTTGACTCAAGGTGCAATTTCAGCAAGTCATTTGTAGCTTTGAATTCTCCKTTTATCCCTTTCTTTGGTGCTATGAGGCTTCAGGAAGCATGGCCAGGCAATTTGGATGAGTGGGTTCAAACACAGCAGAGACTATTCTCAGTTCCCAATA Celera SNP ID: hCV2084298Public SNP ID: rs2853694 SNP Chromosome Position: 158681666 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 21148 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,65|T, 55) SNP Type: INTRON Context (SEQ ID NO: 171):TATCTGCCTTACATTTGACTGAGGATTAAATGAAAAAAAAAAAAAGCACGTAAAGTACTTAGCACAGTGTCTGCCACACAGTAAATTCGGTGTTAGTTATYGTTACTTATAGACTGAGGAGTCAGCCAACTGTACAGAGAAACTCTCTTAACAATTTTCCATGGATATTTAAGGATTTCGTTCCCTCTGTTTTAAATCACC Celera SNP ID: hCV2084301Public SNP ID: rs3213093 SNP Chromosome Position: 158683557 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 23039 SNP Source:dbSNP; Celera; HGBASE Population(Allele, Count): Caucasian (C, 93|T, 27)SNP Type: INTRON Context (SEQ ID NO: 172):TTCATGGAGCCATATTTTCTGGTCATAATTGTGTATCAGGTTCATTCATGCTAATGAGAAAGGGATTCCAGATTTTCTTTGCATCTGTCTGCTTCTCACAKGGCTGTTAAGAAGCCACCTGCCATTCTGACAATTTCATGTCCTTAGCCATAACTACTTGTCCTCTCTCTTGAATCTTAAGATCTTTTTGCCTTCCAGACA Celera SNP ID: hCV7537839Public SNP ID: rs1368439 SNP Chromosome Position: 158674592 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 14074 SNP Source:dbSNP; Celera; HapMap; HGBASE; Population(Allele, Count): Caucasian (G,26|T, 94) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ ID NO: 173):GAAGTCCCACCAAGACTCCCAAGGATAGCGTGTTAGCATACAAGCTGAATAGCCTGTGTTGCAGTCCCTGCTAGTCAGGGTCTTCTGGATAATGCATTGCMTGTGTGAGGACTGGCCTGGTCCTCTGCAGGCTGAATTCTGCATTTAGCAGCTCAGTGTCCCTTCCACGGGCCCCAGTTTCTTCATCAGGAAGGTGAGGGG Celera SNP ID: hCV7537857Public SNP ID: rs983825 SNP Chromosome Position: 158707543 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 47025 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 30|A, 86)SNP Type: INTRON Context (SEQ ID NO: 174):GCTTGTCCCAAATTTCTTTCTATTTGAACTTCCTTGGTGATAAAAATTCTCCTGTGGGAGAATTTTTGTTGTGAACATTTTGGACATTTTGTTGTGTTTGSCTCTAGCTAAAACATGAGCATTTGTTCCTAGAAGGGATAACATTTTTACACTTCTGTTGCCATTAGTATGTGAGCAAGAATTAATATATGAACTCATTGT Celera SNP ID: hCV7538743Public SNP ID: rs1363670 SNP Chromosome Position: 158716689 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 56171 SNP Source:dbSNP; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (G,20|C, 100) SNP Type: INTRON Context (SEQ ID NO: 175):GGAGAGCAGGAGCAGGAGCTGGGGTGATTGCCTTTGGAAGCCATTAGGAACAAACTGTGTACCAGCCTGTGGCAGTGTCTAGGGGTTGTCCATGACCTCTRGAGCCCAAGGGGGCATGTGTTACAAACAATACTCTTTTAGCATTTGCTGTCCACAGACAGCTAAGTGTTTACCCGCTCAGTGGAGGGTTGGGGTGACAGC Celera SNP ID: hCV11269323Public SNP ID: rs11135059 SNP Chromosome Position: 158703915 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 43397 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 81|A, 39)SNP Type: INTRON Context (SEQ ID NO: 176):GGACAGTAGAGGTGCTTTCCTGTGGGATCCCCAATCTCTCCCCGCCTTCAGGTGAGTCCTGCTGATGCTCAGGCTGCCCTTGGAACAGGGACCTTGGCCAYAGTTTCCTTATCTGTAATAATGGGATGAGAATTCCTCCTGCACAGGGTTGTTAGGGACCTCGTGAGGCAGCTTCTATGGCTGCCTTTGGTGCTTAGTTTT Celera SNP ID: hCV11316602Public SNP ID: rs1865014 SNP Chromosome Position: 158671666 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 11148 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 20|C, 94) SNPType: INTRON Context (SEQ ID NO: 177):TTAATGGTTATGGGCCATGCATTGAAGGACCACCCTGTCTGTGCTAATCCCTCACTTTGCACTGAACATGGAACTAAGCTGAGCCTCTCCCTGGGGATGARATGATAGATTTTCTATTTACTGCCCTTTCTTTTGTCTTTTCATAGCTTTTGGTGCGGACATGTCTTGGAGCAGTTACAGTCAATTGTCTCTATGCTCAAT Celera SNP ID: hCV15803290Public SNP ID: rs2421047 SNP Chromosome Position: 158678885 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 18367 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,93|A, 27) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context(SEQ ID NO: 178):GCTCATTTGCTGTTGAGCAGTGGGAGCAACTTGTTGGCCAAGTTACTCGCTGAGCCTCAGTCTCTTTGTCTATAAAATGGACCTAATACTTATCTCAAAGRCTTGTTGGGAAAGGCAATGAGATAACATATTATAGAAGGCAACCAATAACATATTAACTTGAACCTAGAGGAAGAGGTAAGGGAACAATTCGGTATCTGT Celera SNP ID: hCV15894459Public SNP ID: rs2546892 SNP Chromosome Position: 158688053 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 27535 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (G, 103|A,17) SNP Type: INTRON Context (SEQ ID NO: 179):GAGAAACTTCCAGCACAATTTCAGTTTCATAGAGAATACGGCAGGGCACAATATTCAGCAGAGTAACATAGTGGTTAAAAGCTCAGGGTGTCGAGAACAAYGAACCAAGACTGTCATCCTGTCTCCACTAACCAGCTGGGGGATTTGGAACAAGGTATTTCATTATCATGAGCCTCAGTTTCCTCATCTGTAAAATGATAA Celera SNP ID: hCV29927086Public SNP ID: rs3213094 SNP Chromosome Position: 158683347 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 22829 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 93|T, 27)SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO:180): CTCACCTAACTGCAGGGCACAGATGCCCATTCGCTCCAAGATGAGCTATAGTAGCGGTCCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGAMCGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTGTGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCT Celera SNP ID: hCV31985602Public SNP ID: rs3213119 SNP Chromosome Position: 158676366 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 15848 SNP Source:dbSNP; HapMap; HGBASE; Population(Allele, Count): Caucasian (C,115|A, 1) SNP Type: MISSENSE MUTATION; INTRON Context (SEQ ID NO: 181):AACAAGGGGCTTCTTGAGAGGAAATGAAAGGAGACGGAGATGCGGTTTTGCCTTAAGGTTTTTAATGTGAGCCACTGAGAAGATTCATTTTGAAATAGAARGATGTGTCTGACAGTGTGATGTAAATGCAGGCATTTTGGAGTCCCTGCTGGAGAACACACAGAGGTGAGTAGGGGTTCTCCAGTGACCTTGTGGGAGTCT Celera SNP ID: hCV27106385Public SNP ID: rs4244437 SNP Chromosome Position: 158705695 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 45177 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,31|A, 87) SNP Type: INTRON Context (SEQ ID NO: 182):CCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGACCGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTRTGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCTGTTTCTGCAATGCATACTCTCCCAAAACAAGCCCATCTTGGTCTTAGGGCACTGTGCT Celera SNP ID: hCV27106395Public SNP ID: rs11574790 SNP Chromosome Position: 158676424 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 15906 SNP Source:dbSNP; Celera; HapMap; Population(Allele, Count): Caucasian (G, 110|A,10) SNP Type: INTRON Context (SEQ ID NO: 183):TAAAAATCTGGTTAGTGTTGTTCATTAAATGTCCGTTAAGTACTTTGGTAACTGCAGATGAAAGACCCTGTAGGGGGACAAACACTTGTTATTAACAACCRTATGCTGTCAAGTGTGGGCTTATAACACGGGACCATATGCTCCAAAGGTTGGCAAAGAATGACAGAAGCCACCCACCATTCCTCCAGGCCAGGAGCAGAG Celera SNP ID: hCV27467944Public SNP ID: rs3181224 SNP Chromosome Position: 158673428 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 12910 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (A, 110|G,10) SNP Type: INTRON Context (SEQ ID NO: 184):GTAGTGGCTAGATTTACAATAAAAAGGACAGTCCTGGAGACTATCTTTAAAGAAGAAAAACTCTGCATTGCATGCACTGAAATTAATCGAATGCTAAGAGRTCATGTCGCAAAAGCACTGGGCATGGTGGGAGCCAGAACATCTCACCTCTGCCCCAGGCTGGCCAGAAATTTGGGGAAAGGTCCCAGTTCTCAGTGCTTA Celera SNP ID: hCV27467945Public SNP ID: rs3181225 SNP Chromosome Position: 158673201 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 12683 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (G, 102|A,18) SNP Type: INTRON Context (SEQ ID NO: 185):GCAATGCTCAACTGTTTCAGTCAAATACCTTAAAAATGAGCATTCCTGGGTTGGGTGACGGAATATTGACAAATTACAGCTTTGTCAGAACTGCTACTAASTCTAGGCGGACCTTGCTATGTACTTTATTCCCTTATAAAGTTTGTGAGTGGCAGAGACAGGCCTAGAAGTCAAGCCTTCTTGGACACTGCTCAGTGCTGT Celera SNP ID: hCV27471935Public SNP ID: rs3212217 SNP Chromosome Position: 158687708 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 27190 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (G, 93|C, 27)SNP Type: INTRON Context (SEQ ID NO: 186):TGTGTGCTGGAGCACCCAGAACTGAAGGACTTGGGTTAGGGACAGGAACGGTAATACAGAGGCGAACTTTCAGGTTCTGGCAACGACCTGGTCACCAGCCMTTGCTGTAGGGGTTTAGCTTCTCTTGTTTTCCAAGTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGAT Celera SNP ID: hCV27486507Public SNP ID: rs3212219 SNP Chromosome Position: 158687039 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 26521 SNP Source:dbSNP; HGBASE Population(Allele, Count): Caucasian (C, 89|A, 27) SNPType: INTRON Context (SEQ ID NO: 187):GTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGATAACCTGGAAGCACTGCTACAACAGACGGCTGAGTMCCACCCCCAGAGTGTCTGATTCAGCAGGCATGAGGGCCTGAGAATATGCATTTCTAGAAAGTTTCCAGGGGAAGCAGATGCTGCTGGCGCTAAGACCACA Celera SNP ID: hCV27508808Public SNP ID: rs3212218 SNP Chromosome Position: 158687174 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 26656 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 81|A, 25)SNP Type: INTRON Context (SEQ ID NO: 188):AATGAACAGAAAATGGAAGTGAGGTACAGAGACAGCTTGGTTGGTTACAGCTAGGTGTTTGCTTTATTTGAGCATGGTCTGATCAGTTGGTAACCTATAAYTGATTGGAGGTTTGCTGCTGTGTTTTACTGCTGAGGCTCAGCTATTAGCTACAAAAATATATTAAATTAGCTTTCAGTCAGTTCATACCAAGTTAGGTTG Celera SNP ID: hCV28001193Public SNP ID: rs4921466 SNP Chromosome Position: 158665350 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 4832 SNP Source:dbSNP; HGBASE Population(Allele, Count): Caucasian (T, 112|C, 8) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 189):AGTTGGATTCCCCAAAATAATTAGTTAGTTAATTTGTTGACTGATTGATTGACACATTGCTAGCTCCTCTCAGACTGCCCAGTCTTCCTCATGCCCAAAGKGCTCTCATTCTGTTCATGATAACGCCCAAAATCTTTACCTTGGCACACTCGTTTCTCCATGATCTGCCCCTACTCCCTAATCGCTGTCACCTCCTACAAT Celera SNP ID: hCV29349406Public SNP ID: rs6556411 SNP Chromosome Position: 158715801 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 55283 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (G, 32|T, 88) SNPType: INTRON Context (SEQ ID NO: 190):CTGTATGCCCAGCAAAGGGCTGGTGGCTGGAAGGACATAGCTTTCTGAGTTAGGACTGGAAGGCTTCTGTACATGTCCAAAGTCAACCTTCATATTCATGRGGAGGGAAAAAGAAGTGGGCTTTAGGATTGCCTCTCCTTGTTGGCCTGCTCTGAGAAAAACAATCGCGGGAGGGTGAGGCGGGAGAATCGCTTGAGCCCA Celera SNP ID: hCV29349409Public SNP ID: rs6859018 SNP Chromosome Position: 158669570 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 9052 SNP Source:dbSNP Population(Allele, Count): Caucasian (G, 91|A, 27) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 191):CTCTTATTTTTAAGATGAGAAACTTAAAGCTTAGAGAAGGAATGTGACTTTCTGGATCAACATCTAGCAGTTGTTTATTTAGTGCTTACTACATAAAGAGMACTGGGCTAGAAGCAGTTGAGAGAGAAAAAAAGGGCTTACCTGGATCCCGCTTCCTAGGAGCAAATACTTTTACTCAATAAATATTTATTAAGTCAGTGT Celera SNP ID: hCV30449508Public SNP ID: rs3212220 SNP Chromosome Position: 158686773 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 26255 SNP Source:dbSNP; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (C,93|A, 27) SNP Type: INTRON Context (SEQ ID NO: 192):TACTACAGGGGAGAACACTGGTGGACAGACACAACCTAAACAAAGTGATCAAAGTTAATTTCACCAGTACTGAGAGACATTGATTTCATGCCCCTCCTGAYGAGATTCACTGAGAAGGGCACAGTATTACTGCTGTAGGATGCTTGACAAAAATGTAGAACCCAAATTTAATCATGAAGAAACATGAGACAAATGTCACTT Celera SNP ID: hCV29619986Public SNP ID: rs10072923 SNP Chromosome Position: 158668354 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 7836 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 93|C, 27) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 193):TAAATAAAATAAAATAAAGTAGAAAAGAAACAAAAATTATAAGATAGGGACATTAAATGGAGTTAGAAATGAGGCTAATAAATAATGAATATGCTGCACCRTGGAATACTACTCAGCCATAAAACAGAACAAAATAATGGACTTTGCAGCAACTTGGATGGAGCTGGAAGCCATTATCTTAAGTGAAATAATTCACAAATG Celera SNP ID: hCV31985582Public SNP ID: rs6556412 SNP Chromosome Position: 158719963 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 59445 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (G, 79|A, 39) SNPType: INTRON Context (SEQ ID NO: 194):CATTCTCATTTAAATTTGTATATCCCTGATTATTTTTGAGGCCAGGCACCTTCTCAGTCTATCAGTTATCTGTTAAGTTTTGAATCGATTTGTCCATTGGYTGTCTTACCTTATTGATTGGTAGAAGCCCTTAATTTTGGCATGAGCTCTTTATTAGTTACATGTGTGGCAAATATTTTCTCCCACTCAGGGACTTGCTGT Celera SNP ID: hCV30611467Public SNP ID: rs6869411 SNP Chromosome Position: 158714182 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 53664 SNP Source:dbSNP; HapMap; ABI_Val Population(Allele, Count): Caucasian (T, 71|C,49) SNP Type: INTRON Context (SEQ ID NO: 195):ATAGCTTTTCATTTTTTAACTGGGGCCAAAGTTAGTTAATCCACAAGAATGGGGATCCCAGCTGTCATTTTGGTTGATATCACAACTGACGACCAAGACCRTCACAAATATGGGAGCAAGTCTGATTTGTAACATTATTATAATTATGAATCCAATTACTTTAAGGAATGCACGAAAGGCTTTTTAAAAATTTCAATAGTA Celera SNP ID: hDV71045748Public SNP ID: rs6894567 SNP Chromosome Position: 158689546 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 29028 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 94|G, 26) SNPType: INTRON Context (SEQ ID NO: 196):ACAGACCTAGTTAGACCATAGTCCATATTTCAAATATAATTACATGTGCTCATAGCTGAGAACCTTCTCCTGGGATGGATGCATTTCACCAGGTCACTGCYGAAATGTTGTACTTTTATGGATGGTGATGAGGAAGCATCTGTTTTAGGTGTGGTATTTCCTGGAGGCAGAAAACTGCTTGAGTTAGCTCATTCAGTTTTT Celera SNP ID: hCV31985592Public SNP ID: rs7709212 SNP Chromosome Position: 158696755 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 36237 SNP Source:dbSNP; HapMap; ABI_Val Population(Allele, Count): Caucasian (T, 76|C,44) SNP Type: INTRON Context (SEQ ID NO: 197):AAAACATATGGGTTGGGTTATCCACTTCAATGACTGCACATTAAGCAAGAGTATAGTGTACCATGTTTTATTTAACCATTCCTCTGCTGATTATGTCTTTWTGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAATGGTAAAGTCA Celera SNP ID: hDV75439995Public SNP ID: rs3213097 SNP Chromosome Position: 158681257 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 20739 SNP Source:CDX; dbSNP Population(Allele, Count): Caucasian (T, 89|A, 27) SNP Type:INTRON Context (SEQ ID NO: 198):GTGATTCAGATCTGGGATGGGGCTCAGGAACCTGCATTTTAACAATGGAGGTTCTAATGTGGTCATTGGCAGGTTGTTCTAATGTGGGGGCCACATTAGAG /TTAGACCTCTCTCGGAGACAGGCTGTACATGGCCAGCCAGCATTCTGGTAATATGAGCCAAATGCCCATTGACCTAATTTTGGAGAAGAGGTTTATCAACATGTC Celera SNP ID: hDV79877074Public SNP ID: rs17860508 SNP Chromosome Position: 158692783 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 32265 SNP Source:dbSNP Population(Allele, Count): no_pop (G, —|, —) SNP Type: INTRONICINDEL Context (SEQ ID NO: 199):CCATATCAGGTGTTGATGGTGAAGGGGTGCTGTGTTTCTTTTTGGGGTATTGAAAATATTCCAGAATTTATTGTGGTGATGGGAGCACAACTCTGTAAGTSTATAAAACCTGTTGAATTAGACACCTTAAAAGAGTCACTTGTAGAGTATGTGAACTATACCTCATTACAGCTGTTAGAAAAATGTATACCTTGGTGGTCA Celera SNP ID: hCV2084282Public SNP ID: rs2099327 SNP Chromosome Position: 158663429 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 2911 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; Celera;HGBASE Population(Allele, Count): Caucasian (G, 100|C, 20) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 200):AATATCTGATTGTGTTACTTCCTTGCTGAAAACCCTTCAGTGGGTTTCAGGGCCCGGGGCCCCCAGAACAAGATTCTGAGTCCTGCAAGCTTGCAAGTCCKCCATGCTCTGCCTCCTGGCTACCTCTCTCTTTTCTTTGCCTTTCTCTTTAGGAGGCCAGAACCCCGGTCTGTTTTCTTTCCTGCAATATCCCTGTGGCCA Celera SNP ID: hCV15824051Public SNP ID: rs2853697 SNP Chromosome Position: 158675981 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 15463 RelatedInterrogated SNP: hCV15894459 (Power = .51) Related Interrogated SNP:hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap; HGBASEPopulation(Allele, Count): Caucasian (T, 102|G, 18) SNP Type:TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 201):TGGAGGTTAACATCAATTAACATCAATAAGAGACTTGATGTTAATTCATTACACTCACCATGACTTGGCTTTTCAATTTGTTGTTGTTGTTGTTTTTAACYCTTATGAGCGAAAGAGAAAATTGATACTATCCAAGGGTATAGAATTACCTTTCTGGTCCTTTAAAATATCAGTGGACCAAATTCCATCTTCCTTTTTGTG Celera SNP ID: hCV15879826Public SNP ID: rs2288831 SNP Chromosome Position: 158682591 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 22073 RelatedInterrogated SNP: hCV2084270 (Power = .51) Related Interrogated SNP:hCV2084293 (Power = .51) Related Interrogated SNP: hDV71045748 (Power= .51) SNP Source: dbSNP; HapMap; ABI_Val; HGBASE Population(Allele,Count): Caucasian (T, 91|C, 25) SNP Type: TRANSCRIPTION FACTOR BINDINGSITE; INTRON Context (SEQ ID NO: 202):TGAAGCAGTCCAGTAGAGCTTAGTCTTCCCATTTAATGAAGAAGCGTACTGAGGCCAACGATCTAAGCATGGTCACAGCAAGTCAGAAGTACAAGGGCTAYAGCTCAGACCTTTTGTCTCTTGGGCTTTGCAAGGGATGCCTAATGCTAGTGTCTAAACTGGCCTTTGAGGAATGGCTTAGTATAGTATTTCAGAGTGTGT Celera SNP ID: hCV16044033Public SNP ID: rs2569254 SNP Chromosome Position: 158683827 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 23309 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap;HGBASE Population(Allele, Count): Caucasian (C, 102|T, 18) SNP Type:INTRON Context (SEQ ID NO: 203):TCACAAGTCTGTTATGTAACCATAGTTGGGACTGGAGTCTGCTCCTCTGATTCCCAGTCCTAAGATCTTTGGCTTAGACATTTAGTACATTTTGTAGTGGSTAGATTTACAATAAAAAGGACAGTCCTGGAGACTATCTTTAAAGAAGAAAAACTCTGCATTGCATGCACTGAAATTAATCGAATGCTAAGAGGTCATGTC Celera SNP ID: hCV27467946Public SNP ID: rs3181226 SNP Chromosome Position: 158673108 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 12590 RelatedInterrogated SNP: hCV15894459 (Power = .51) Related Interrogated SNP:hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap; ABI_Val; HGBASEPopulation(Allele, Count): Caucasian (G, 102|C, 18) SNP Type: INTRONContext (SEQ ID NO: 204):TTATGTCTTTATGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAAWGGTAAAGTCAGGATGATCACCTGGGGTTTGCTTCGGTGATGATTAAAGTAAGCCACATGGGGGTTAACACATAGGTCTTGTATTTATGGAAGTTGCTTTC Celera SNP ID: hCV32389155Public SNP ID: SNP Chromosome Position: 158681347 SNP in GenomicSequence: SEQ ID NO: 17 SNP Position Genomic: 20829 SNP Source: HGBASE;dbSNP Population(Allele, Count): no pop (A, —|T, —) SNP Type: INTRONContext (SEQ ID NO: 205):TACCTCCCAACAGTCCTGTGAATTTACTATGCTACCCCAGGGTGACCTGGTAGAGAGTTTGGAACCACAGCTAGCCATAGTACTTTCAAACTACTAAAGTYAGATATCTCTTTGCCACCAAATCCCTCCTCAGGGCCATATGTGACCCTGCATTTTGTGCAGGGATTCCAGGAAGCAAAGTTGTCACTCTTTCTGGAAACT Celera SNP ID: hCV31985590Public SNP ID: rs11738529 SNP Chromosome Position: 158702844 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 42326 RelatedInterrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (T, 64|C, 46) SNP Type: INTRONContext (SEQ ID NO: 206):AGTGACAATTACATATCAGGCACCCAGCTAAATTCTGTGAATGTAGTAAGCAGATCAGACCTGGACTCTGTCCTCATAGAGCTAAATAGATATGTGCAGARGACAAAATGCTATGAAGGAAATGAATGGGTGGTGAGACAGAGAATCACAGGGGAGGGCTCTCTGATGAGGTGGCATTTAAGTTGGGACCTACAGGTGAAC Celera SNP ID: hDV70836316Public SNP ID: rs17056705 SNP Chromosome Position: 158701831 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 41313 RelatedInterrogated SNP: hCV11314640 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (G, 112|A, 8) SNP Type: INTRONContext (SEQ ID NO: 207):CCTGCCAGAAGGCAATTAAAGAGTGGAAGAGCAGAAATGCAGAGAAGGAATTCAACACCTGCTCCACCAGCACGTTCCTTGGTCGCTCTCGTCTGTTTCCYTAGCTGGATCACATTCTTGGTGAATGAGAGAAAGTATGAGGATTAATGAGCAGACCTGTCTTTGGGATACCCTAGAACCATGATGCAATGCAAATATCAC Celera SNP ID: hDV70836317Public SNP ID: rs17056706 SNP Chromosome Position: 158703333 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 42815 RelatedInterrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (C, 69|T, 49) SNP Type: INTRONContext (SEQ ID NO: 208):GGATGAGTCTCACTTAGTCATGAAATGCAGTCTCTTTGTATGTTGCTGGATTTAGTTTGCTAGTACTTTGTTGAGAATTTGTGCCTCCATATTCTTAAGTRATTTTGGTCTGCAGTTTTTTTTTTGAGATGTGTTTGTCTGGTTTTGATATCAGGGTAATACTAATTTCATAGAATAAGTTAAGAAGTGTTTCCTCCTCTT Celera SNP ID: hCV31985588Public SNP ID: rs6878967 SNP Chromosome Position: 158711610 SNP inGenomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 51092 RelatedInterrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP; HapMap;ABI_Val Population(Allele, Count): Caucasian (A, 71|G, 49) SNP Type:INTRON Gene Number: 6 Gene Symbol: hCG2038173 Gene Name: Chromosome: 5OMIM NUMBER: OMIM Information: Genomic Sequence (SEQ ID NO: 18): SNPInformation Context (SEQ ID NO: 209):CTGTGTGCCCAGCACTTCCTCTGCATGCCTCAGATGCATTTGACAATCTCAGGTGAACTGCACTTCAGGGTCAAGGGAACCCCGGCCATGGTTCTAAGAARCAACTCCCATTTTAGTATCACCTACATTTGAAACCACAGAGCACTGTCCAGGAGAGGTGATGGTGGTGGGTCTCCTCCTTTGGCTCTCTGGCCCATCAGC Celera SNP ID: hCV1992693Public SNP ID: rs1433048 SNP Chromosome Position: 158688423 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 15090 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (G, 21|A, 99) SNP Type: INTRON Context (SEQ ID NO: 210):TGGACAGATGAAGGCTGGTACTCATGCTTCTTCCCACTGCAAGAAGAGGAGCCATGTGTCATTTCCTCTCTGTGACTGTGAGCAGCCCTTGGCCCCTGGARCTCCCCAGGTACAACCGGAACAACATCATGGTGCACTGGGCTTACTTTTAAGCCTAGAACATGAAGAGAGCTGGTTAGAAGGGGACAAGCAAAGGACTGG Celera SNP ID: hCV1994960Public SNP ID: rs4921483 SNP Chromosome Position: 158700943 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 27610 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,19|G, 99) SNP Type: INTRON Context (SEQ ID NO: 211):TCAAAGCAGAACCTTAGGCTCTAAGGGAAACAAGACAGAAGGATTCTGCTGACAAGACAGTAAAGTAGCCTGCTCATCTGGTGGTAGGCACTGTGTCAGCRTTCTAGGTTGTAAATGTAGGAAGTAAGCAGATCAGAGGTTTGCTCAACAACCTGCCTAGTGAGCCAAACTGCTTGCTCTTGAGGCCATGTAGTCCTTCTG Celera SNP ID: hCV1994965Public SNP ID: rs953861 SNP Chromosome Position: 158705160 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 31827 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (G,20|A, 100) SNP Type: INTRON Context (SEQ ID NO: 212):CCTGACCTTGTGATCCTCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGGCACCGCGCCAGGCCTATTGTCTCTTTAATACCTCTCTATCAYTTGTTGATCTCTCTTCTTAAGGAGGGCAAGCACTCTTCAGCCTTAGAGGCATTAGCAGGCAACAGCATCTATTCTAGTGGATCTCATCCTTGGCTGCATG Celera SNP ID: hCV1994966Public SNP ID: rs11746138 SNP Chromosome Position: 158706357 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 33024 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 108|T,12) SNP Type: INTRON Context (SEQ ID NO: 213):TCCTGTCTTCTTTAGGCCCAGTTTCCTCAACAATGAAATGGGACTAATTATCCCAGGTCACACTTCTCTCTGGGCTTACCCTGGGAATCAGATGATTGAGSTTTGGTAAGTATTATTTGATAAACAAGTATGAGGAAGGAAATAAAAGGGAGATCAGTGCTGCAGAGATGGCTAATTGGCAGATTTACACAGAACTGGATT Celera SNP ID: hCV1994967Public SNP ID: rs11747112 SNP Chromosome Position: 158707187 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 33854 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 108|G,12) SNP Type: PSEUDOGENE Context (SEQ ID NO: 214):CTTCTTTATTTTCTCAACAATGTTTTGCAGTTCTCAGCATATAACTTTCATTTCTTTTGTTCAATTTATTCCTAAGTATTTAATACTTTTTGGTGCTATTKCAGATGAATTTTCCTATTAATTTTCATATTGGTCATTGCAATTGTATAAAAATACAATTATTTTTGTATATTGATCTTGTTTCATGCAATCTTGCTGTGA Celera SNP ID: hCV1994971Public SNP ID: rs7725339 SNP Chromosome Position: 158709579 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 36246 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 73|T, 35)SNP Type: INTRON Context (SEQ ID NO: 215):ATGAGGTGCCCTGTGGGGTTAAACAGAAATGAGAGATGCAAAGAGTGTAAGGTGGCATTTCCATTTCTGGTCTCTGAGCTCTACCTTTATGCACTGTTTTRGCTGTTCAGTCTTTATCTAAATAACTTCTAATAACTCCACTGCCACCGCCATCTAGCTATGCTCTTGGGTAATTTGAGTTGAATTTTTGTCACATGCAAC Celera SNP ID: hCV1994973Public SNP ID: rs1157509 SNP Chromosome Position: 158718688 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 45355 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,20|G, 100) SNP Type: INTRON Context (SEQ ID NO: 216):GGGGTTAAACAGAAATGAGAGATGCAAAGAGTGTAAGGTGGCATTTCCATTTCTGGTCTCTGAGCTCTACCTTTATGCACTGTTTTAGCTGTTCAGTCTTYATCTAAATAACTTCTAATAACTCCACTGCCACCGCCATCTAGCTATGCTCTTGGGTAATTTGAGTTGAATTTTTGTCACATGCAACTGAGAGTCCTGACT Celera SNP ID: hCV1994974Public SNP ID: rs1157510 SNP Chromosome Position: 158718702 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 45369 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T,20|C, 100) SNP Type: INTRON Context (SEQ ID NO: 217):AAAAAACAAATAATTGCATCAAAAAGTGGGCAAGAGACATGAATAGCGAATTCTCAAAAGAAAATATACAAACAGCCACCAAACATATGAAAAAATGCTCRACATCACTAATTATCAGGGAACTGCAAATTAAAACCACAATGAGATACCACCTTACTCATGCAAGAATGGCCATAATTAAAAAGTCAAAAAATAATAGAT Celera SNP ID: hCV1994986Public SNP ID: rs11749573 SNP Chromosome Position: 158743793 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 70460 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (G,20|A, 100) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 218):CACTAATATGAGAACAATCTCTTTAGGACTGGAAACCACGAAGTCAATTGAATTGAATGCACCACAACCCAGTGAGTTAAATCTTTGTGGAAAGATTCCASAAATGCCTCTAAAGTTGCATCTATAAGCTTAATGATCTTATGTCTGTGTCTCCATGGATGCCAAGTGATATGATTTGGATCTCTATCCCCACCCAAATCT Celera SNP ID: hCV1994990Public SNP ID: rs6861600 SNP Chromosome Position: 158752193 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 78860 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (C, 82|G, 38) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 219):CTGACTTGCTTCATACTTCTTCCTGCCTCCGCTAGCCTCCACCCAGGGAAGGTGTGCTTCTCGGTAAGTCAGTTTGAGAGAAGCAGTGTAGTGTAGTGGTSAATAGTCTGGATTTACATCTTTGATCTTCCATTTACTACGCTTGTGACCTAGGGGGTGTTGCTTCCCCTCTCTGTTCCAATTATTTATCCATAAAATAGA Celera SNP ID: hCV1994992Public SNP ID: rs6887695 SNP Chromosome Position: 158755223 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 81890 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (G,82|C, 38) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 220):TAAATTTCCAACTCATGCCTTTTGGGGGACACATTCAAACTATAGCAAATACTAAGTTAAGGAAGTTTCAGCTCTGTCTGGCAGCCTCATAATATTTCAAYGCTTCATCATTTGAATGCTTATTAATTAACCAACTTCCTGTATGCCATGTGATCAGATGTCACAAGAGGAGTTCCTTTGGGATGAACTTAGTTCTTTGTG Celera SNP ID: hCV1995017Public SNP ID: rs4921496 SNP Chromosome Position: 158780649 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 107316 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (T, 27|C, 93) SNP Type: INTERGENIC; UNKNOWN Context (SEQ IDNO: 221): GCTGGAATTCAGATCCCAGGTCTGTCAAAGCCTAATCCCAGCCAGCCTTCCTTCTGTTGCTCCAACGGGGAGTCCTACTCAAAACTGTTCCTGGTCCTGTRTGACAGCATTGATAAGACTCCTGGAAATTTTTGTTACTTCCTAGCCTCCACTTTCTACCTTCCCATTTTCTCCTAATTTTCTCAATCTTTGTTGGGGTTT Celera SNP ID: hCV1995018Public SNP ID: rs4921500 SNP Chromosome Position: 158783091 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 109758 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,27|G, 93) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 222):CTGGTTCTTTCCCATCAGTGCTGTCACCAAAGAGAACCACCATTTTCATATTATCTGTTTTCGAACTCATATAAATGGAATCGTAGAGCATGCGTTCATTKTGTCTAACTTCTTTTGTTCAAAATTATGTCTGGGAGATTCATCCATGTTCTAGCATGTAGGAGCCGCCCACCCTTTTTCATTGCTGTGTAGTATTCTGTT Celera SNP ID: hCV1995024Public SNP ID: rs7702534 SNP Chromosome Position: 158790051 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 116718 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (T, 26|G, 90) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 223):AAGTCATAAAGCTGAAGAAACTTCTGGGTGTTCAGTGAGTAAATGAATGTTTGAGTGCAATGTGGAGACAGAATCATCATTGCACGTCTTATTTATAATTMGGATTGTTCATCAGGTTGACCTTGAATCATGGATCCCATAACAGAAAGTTAGATACGGCTGCTTTGAGAACTAAAAGGCCCAAAAAGTGCAGTCAGATCC Celera SNP ID: hCV1995530Public SNP ID: rs2421186 SNP Chromosome Position: 158850858 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 177525 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,84|C, 28) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 224):AATTACTTAAATATTTAAATAGCATGAAGGCCCATGGCAACTTGAGAGCTGGAAAATCTATACATAAATTAGCTGATTGTTTCAATGAGCATTTAGCATCKAACTATACAAATACAGCAAAGATATCATTGTGATCCTAAAAAAACGTTTTAAAGCAAATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTT Celera SNP ID: hCV2084293Public SNP ID: rs3212227 SNP Chromosome Position: 158675528 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 2195 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (T,93|G, 27) SNP Type: UTR3; INTRON Context (SEQ ID NO: 225):ATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTTTAAACATTTTGCTTAATATCTTCCACTTTTCCTCCAAATTTTCATCCTGGATCAGAAYCTGGAAGAGAATGCCAAAAGTTGATGTGGGGTGACATTGTAACAGCAATGTCTCTTCTTATTTCTCACAACATATGATCCTGGGCAACTGGGTTTCAGGG Celera SNP ID: hCV2084294Public SNP ID: rs3213120 SNP Chromosome Position: 158675686 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 2353 SNP Source:dbSNP; Celera; HapMap; HGBASE; Population(Allele, Count): Caucasian (C,117|T, 3) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ ID NO: 226):GGAAAATGTCTTAGGTTCTCTGTGTCTGTTTCCTCACTTATAAATAGGGATAACAATAATGCCTACTTCATAGAATTATAGTTCAAGGTAAAAATCACGTYAAACTCTTAGCAAGTCTTTAGCACATAGGAAGCACTCAATATCACCTATTAGTCATACAGATCTTAAATAGGGAAAGTACTTGCCAAGATGTAAAATAAT Celera SNP ID: hCV2084295Public SNP ID: rs2195940 SNP Chromosome Position: 158676930 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 3597 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (C,110|T, 10) SNP Type: INTRON Context (SEQ ID NO: 227):GGCTTTGTCCAGTGATTTTAAAAGTGGGGTGAAAGGAGTCTGGGGCGGTACAAAAGGGCCTCTGGAACCTTGCAACAGGCAAAGGAATTCTGCTGTAAGGYGAGGAAGCTGGGAAGCCAATATCTTAGCCTCTATAAGTGTAGACATTCTGTTTAGTAAAATAATTTTATAATATCTGGAACAGCCAGGAGCTATCCATTT Celera SNP ID: hCV2084296Public SNP ID: rs2853696 SNP Chromosome Position: 158677238 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 3905 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (T, 26|C, 94) SNP Type: INTRON Context (SEQ ID NO: 228):CCCCTCTGACTCTCTCTGCAGAGAGTGTAGCAGCTCCGCACGTCACCCCTTGGGGGTCAGAAGAGCTGAAGTCAAAGACAGAAATTAGCCTGTGTTACACMTTGGGGAGAGAGTTCCTAGTGATTGTAGCCAGTAAGGCAGGTAAGGCCTCAACTGTTGTCTGAGGACACAGTTTCTCCAACTGGGCTGATTTCTACCCAG Celera SNP ID: hCV2084297Public SNP ID: rs919766 SNP Chromosome Position: 158680142 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 6809 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,110|C, 10) SNP Type: INTRON Context (SEQ ID NO: 229):GTCTGCTTCAGGGCCCCTAAGATCTACGCCCTGGAGCTCTTGTTTTTATTTTTGACTCAAGGTGCAATTTCAGCAAGTCATTTGTAGCTTTGAATTCTCCKTTTATCCCTTTCTTTGGTGCTATGAGGCTTCAGGAAGCATGGCCAGGCAATTTGGATGAGTGGGTTCAAACACAGCAGAGACTATTCTCAGTTCCCAATA Celera SNP ID: hCV2084298Public SNP ID: rs2853694 SNP Chromosome Position: 158681666 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 8333 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,65|T, 55) SNP Type: INTRON Context (SEQ ID NO: 230):TATCTGCCTTACATTTGACTGAGGATTAAATGAAAAAAAAAAAAAGCACGTAAAGTACTTAGCACAGTGTCTGCCACACAGTAAATTCGGTGTTAGTTATYGTTACTTATAGACTGAGGAGTCAGCCAACTGTACAGAGAAACTCTCTTAACAATTTTCCATGGATATTTAAGGATTTCGTTCCCTCTGTTTTAAATCACC Celera SNP ID: hCV2084301Public SNP ID: rs3213093 SNP Chromosome Position: 158683557 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 10224 SNP Source:dbSNP; Celera; HGBASE Population(Allele, Count): Caucasian (C, 93|T, 27)SNP Type: INTRON Context (SEQ ID NO: 231):GTGAGGGTCCAGAAACTTGTATGATCCAGGTATTCGTTTATTGATTTTTTTTCAAGTAATTAGTGAGCATTTACCATGTATGAAGTGCTGAGGATAAATARTGAGCAAGGCAAGCAGGCTTCTGCCCTCACAAAGCTCATATTCTAGTCCTGCGTATGTGTGTTGGTGGGGGAAATGTAAACAATATACAAGTAAACAAAC Celera SNP ID: hCV3169817Public SNP ID: rs4921499 SNP Chromosome Position: 158781130 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 107797 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,26|G, 92) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 232):TTCATGGAGCCATATTTTCTGGTCATAATTGTGTATCAGGTTCATTCATGCTAATGAGAAAGGGATTCCAGATTTTCTTTGCATCTGTCTGCTTCTCACAKGGCTGTTAAGAAGCCACCTGCCATTCTGACAATTTCATGTCCTTAGCCATAACTACTTGTCCTCTCTCTTGAATCTTAAGATCTTTTTGCCTTCCAGACA Celera SNP ID: hCV7537839Public SNP ID: rs1368439 SNP Chromosome Position: 158674592 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 1259 SNP Source:dbSNP; Celera; HapMap; HGBASE; Population(Allele, Count): Caucasian (G,26|T, 94) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ ID NO: 233):GAAGTCCCACCAAGACTCCCAAGGATAGCGTGTTAGCATACAAGCTGAATAGCCTGTGTTGCAGTCCCTGCTAGTCAGGGTCTTCTGGATAATGCATTGCMTGTGTGAGGACTGGCCTGGTCCTCTGCAGGCTGAATTCTGCATTTAGCAGCTCAGTGTCCCTTCCACGGGCCCCAGTTTCTTCATCAGGAAGGTGAGGGG Celera SNP ID: hCV7537857Public SNP ID: rs983825 SNP Chromosome Position: 158707543 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 34210 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 30|A, 86)SNP Type: INTRON Context (SEQ ID NO: 234):GCTTGTCCCAAATTTCTTTCTATTTGAACTTCCTTGGTGATAAAAATTCTCCTGTGGGAGAATTTTTGTTGTGAACATTTTGGACATTTTGTTGTGTTTGSCTCTAGCTAAAACATGAGCATTTGTTCCTAGAAGGGATAACATTTTTACACTTCTGTTGCCATTAGTATGTGAGCAAGAATTAATATATGAACTCATTGT Celera SNP ID: hCV7538743Public SNP ID: rs1363670 SNP Chromosome Position: 158716689 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 43356 SNP Source:dbSNP; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (G,20|C, 100) SNP Type: INTRON Context (SEQ ID NO: 235):TGCTTACTAGAGACCAAAATGCCAAGATTTCAACGGGAGCCAGCCACCCTGGTTTCTATTTTGATGTGATTACTTAGTCATTTAAAGTCAGGTTAATGTTSGCCAACAACAGATGGGGTCAGGACACAGGAGTTCTGCAGCTCACTGAAACTGGACAGTCTTTTAGGGCACCCAGCTCACAAGGCCACACCGTGGCCCGCC Celera SNP ID: hCV7538755Public SNP ID: rs918520 SNP Chromosome Position: 158758888 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 85555 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (C, 20|G, 100) SNP Type: INTERGENIC; UNKNOWN Context (SEQ IDNO: 236): TGTTTTAGGATCAAAATAATGAAAAAGAATAGAAACCATTTCAACTCAGAAAATAATTCAAAGATGGGAAAAAGGTGTGTACCAAATTCATTGCTCTAATYATTTCTGTTCTGATAAAAGGAGTTTACAGCAAAGGAATAACTTTTCTGTGTCTCTGAGGCTTTGGAAAAACAAGGCATCAAGAAGCTTTGGGGTGTGGTG Celera SNP ID: hCV7538761Public SNP ID: rs1422878 SNP Chromosome Position: 158771795 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 98462 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (C, 68|T, 52) SNP Type: INTERGENIC; UNKNOWN Context (SEQ IDNO: 237): GGTAAACCATGGATGTGGTTCTACAGATGTTGCCACAACAGGAAGACAAAATCTCACAGCTAACAGAGGTCACAGCTTTTGGAAACAGTGGTTGCGACACRGAGGAAACTCCCCCTCCCAGCCCTACCCCAAGCACATCCTTGCTTCTCTCAGTCACGCCAGTTACACCAACAGGGGCAGCTCTGGGGAGGACATTTGGAA Celera SNP ID: hCV7538765Public SNP ID: rs1422877 SNP Chromosome Position: 158772090 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 98757 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (A,57|G, 51) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 238):CCATTTCAACTCAGAAAATAATTCAAAGATGGGAAAAAGGTGTGTACCAAATTCATTGCTCTAATCATTTCTGTTCTGATAAAAGGAGTTTACAGCAAAGRAATAACTTTTCTGTGTCTCTGAGGCTTTGGAAAAACAAGGCATCAAGAAGCTTTGGGGTGTGGTGGGTGTGGTGGGGCAGCCTACTGCTTGTTGAGGTAA Celera SNP ID: hCV11264606Public SNP ID: rs1984811 SNP Chromosome Position: 158771830 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 98497 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,20|A, 76) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 239):CTTTGTAATGTGCTATTGAATTTGATTTGCTAGTATTTTGTTGAGGATTTTTGCATCTATGTTCATCAGGAATATTGATCTATAGTTTTATTTTTTTGCTRTGTCCTTGTCTGGTTTTGGTATTAGGGTGATATTGATCTCATAGCATGAATTAGGGATAATTCCTTCCTCCTCAATTTTTTTTTAATAGTTTCAGGAAGA Celera SNP ID: hCV11264637Public SNP ID: rs6864071 SNP Chromosome Position: 158733765 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 60432 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (G,81|A, 39) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 240):GGAGAGCAGGAGCAGGAGCTGGGGTGATTGCCTTTGGAAGCCATTAGGAACAAACTGTGTACCAGCCTGTGGCAGTGTCTAGGGGTTGTCCATGACCTCTRGAGCCCAAGGGGGCATGTGTTACAAACAATACTCTTTTAGCATTTGCTGTCCACAGACAGCTAAGTGTTTACCCGCTCAGTGGAGGGTTGGGGTGACAGC Celera SNP ID: hCV11269323Public SNP ID: rs11135059 SNP Chromosome Position: 158703915 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 30582 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 81|A, 39)SNP Type: INTRON Context (SEQ ID NO: 241):TTTGGGTGGCCTCAGCTTCCTTTTTTTTTTCTTTGTATATTCTAAGTGGATGCTTGAAGTCATTTCATTTATTGACATTGTCAGAATCAAAATGTGGTGAYATGAAATCAGTCAGGGCCAAAGTTGTTGTACTCAGAAACGTAGTATAAATCATGCAAACACTATATAAAGCACATTTCAAATGAATCAGGTATTTAAAAC Celera SNP ID: hCV11314640Public SNP ID: rs1833754 SNP Chromosome Position: 158751505 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 78172 SNP Source:dbSNP; Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count):Caucasian (T, 112|C, 8) SNP Type: INTERGENIC; UNKNOWN Context (SEQ IDNO: 242): TTAATGGTTATGGGCCATGCATTGAAGGACCACCCTGTCTGTGCTAATCCCTCACTTTGCACTGAACATGGAACTAAGCTGAGCCTCTCCCTGGGGATGARATGATAGATTTTCTATTTACTGCCCTTTCTTTTGTCTTTTCATAGCTTTTGGTGCGGACATGTCTTGGAGCAGTTACAGTCAATTGTCTCTATGCTCAAT Celera SNP ID: hCV15803290Public SNP ID: rs2421047 SNP Chromosome Position: 158678885 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 5552 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,93|A, 27) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context(SEQ ID NO: 243):GCTCATTTGCTGTTGAGCAGTGGGAGCAACTTGTTGGCCAAGTTACTCGCTGAGCCTCAGTCTCTTTGTCTATAAAATGGACCTAATACTTATCTCAAAGRCTTGTTGGGAAAGGCAATGAGATAACATATTATAGAAGGCAACCAATAACATATTAACTTGAACCTAGAGGAAGAGGTAAGGGAACAATTCGGTATCTGT Celera SNP ID: hCV15894459Public SNP ID: rs2546892 SNP Chromosome Position: 158688053 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 14720 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (G, 103|A,17) SNP Type: INTRON Context (SEQ ID NO: 244):GAGAAACTTCCAGCACAATTTCAGTTTCATAGAGAATACGGCAGGGCACAATATTCAGCAGAGTAACATAGTGGTTAAAAGCTCAGGGTGTCGAGAACAAYGAACCAAGACTGTCATCCTGTCTCCACTAACCAGCTGGGGGATTTGGAACAAGGTATTTCATTATCATGAGCCTCAGTTTCCTCATCTGTAAAATGATAA Celera SNP ID: hCV29927086Public SNP ID: rs3213094 SNP Chromosome Position: 158683347 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 10014 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 93|T, 27)SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO:245): CTCACCTAACTGCAGGGCACAGATGCCCATTCGCTCCAAGATGAGCTATAGTAGCGGTCCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGAMCGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTGTGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCT Celera SNP ID: hCV31985602Public SNP ID: rs3213119 SNP Chromosome Position: 158676366 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 3033 SNP Source:dbSNP; HapMap; HGBASE; Population(Allele, Count): Caucasian (C,115|A, 1) SNP Type: MISSENSE MUTATION; INTRON Context (SEQ ID NO: 246):CCAATACAGGAGAGAGCTGAAGGGAATTCCCAGGCTGATGGTGAAAGATGGCCCACAATGACAGCTGTTTGGCAGGTCTAGAAACCCATTACAGGTTGAARGGAAAAGGTGGAAGTCTCCACGGTGGATGTTCCTAAGAAGAGTGGAACTGAGAGACTACTAATGGATTCAGGTATATTGAGAGAAATTCTTAGGGCTCCA Celera SNP ID: hCV27106331Public SNP ID: rs12657996 SNP Chromosome Position: 158836891 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 163558 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 72|A, 26)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 247):TAAGGCTTCCAGTCAATAGAAGGCTGTTATTAGTTAAGTTCTGGCTGAGTCAAAAGTGATACATAAATTTTCAACTGCATGGTGGGGTCAACATTACTAAMCCCCTCACCCTTCATGGGTGAACTGTATTTTTATATCTATATCTAATCTATATATCTATATATCTCTCTATATATATTTAGTTTGGGTGGCCTCAGCTTC Celera SNP ID: hCV27106358Public SNP ID: rs6556416 SNP Chromosome Position: 158751323 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 77990 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (A, 32|C, 86) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 248):ATGATTTATGAAGAAAAAGAGGTTTAATGGACTCACAGTTCCACGTGGCTGGAGAGAGCTTACAATCATGGTGGAAGGTGAAGGAGGAGCAAAGCCATGTYGTACATGGAGGCAGGCAAGAGAGTGTGTGCAGGGGAACTTCCCTTTATAAAGCCATCGGATCTCGTGAGACTTATTCGCTATCACGAGAAGAGCATTGGA Celera SNP ID: hCV27106359Public SNP ID: rs12522665 SNP Chromosome Position: 158750818 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 77485 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 76|T, 34)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 249):TATTGGCCTGAAGCCTGAATCATCAACTCAGTAAATAAAATACTGGGAACAATTAAACAAATAAAGTGAATACTATGAGAGAATGAGATAAGCCTCAAGAKATTGCTACCATTCCAGCCCCATAGGACACAGTGAACTGGCCCACACTCCAAGTACCTAACTACTACAACCAGAGCACAAAGACTCTCTATGATAAAGGAA Celera SNP ID: hCV27106365Public SNP ID: rs4379175 SNP Chromosome Position: 158737506 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 64173 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (G,81|T, 39) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 250):AACAAGGGGCTTCTTGAGAGGAAATGAAAGGAGACGGAGATGCGGTTTTGCCTTAAGGTTTTTAATGTGAGCCACTGAGAAGATTCATTTTGAAATAGAARGATGTGTCTGACAGTGTGATGTAAATGCAGGCATTTTGGAGTCCCTGCTGGAGAACACACAGAGGTGAGTAGGGGTTCTCCAGTGACCTTGTGGGAGTCT Celera SNP ID: hCV27106385Public SNP ID: rs4244437 SNP Chromosome Position: 158705695 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 32362 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,31|A, 87) SNP Type: INTRON Context (SEQ ID NO: 251):CCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGACCGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTRTGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCTGTTTCTGCAATGCATACTCTCCCAAAACAAGCCCATCTTGGTCTTAGGGCACTGTGCT Celera SNP ID: hCV27106395Public SNP ID: rs11574790 SNP Chromosome Position: 158676424 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 3091 SNP Source:dbSNP; Celera; HapMap; Population(Allele, Count): Caucasian (G, 110|A,10) SNP Type: INTRON Context (SEQ ID NO: 252):TAAAAATCTGGTTAGTGTTGTTCATTAAATGTCCGTTAAGTACTTTGGTAACTGCAGATGAAAGACCCTGTAGGGGGACAAACACTTGTTATTAACAACCRTATGCTGTCAAGTGTGGGCTTATAACACGGGACCATATGCTCCAAAGGTTGGCAAAGAATGACAGAAGCCACCCACCATTCCTCCAGGCCAGGAGCAGAG Celera SNP ID: hCV27467944Public SNP ID: rs3181224 SNP Chromosome Position: 158673428 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 95 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (A, 110|G,10) SNP Type: INTRON Context (SEQ ID NO: 253):GCAATGCTCAACTGTTTCAGTCAAATACCTTAAAAATGAGCATTCCTGGGTTGGGTGACGGAATATTGACAAATTACAGCTTTGTCAGAACTGCTACTAASTCTAGGCGGACCTTGCTATGTACTTTATTCCCTTATAAAGTTTGTGAGTGGCAGAGACAGGCCTAGAAGTCAAGCCTTCTTGGACACTGCTCAGTGCTGT Celera SNP ID: hCV27471935Public SNP ID: rs3212217 SNP Chromosome Position: 158687708 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 14375 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (G, 93|C, 27)SNP Type: INTRON Context (SEQ ID NO: 254):TGTGTGCTGGAGCACCCAGAACTGAAGGACTTGGGTTAGGGACAGGAACGGTAATACAGAGGCGAACTTTCAGGTTCTGGCAACGACCTGGTCACCAGCCMTTGCTGTAGGGGTTTAGCTTCTCTTGTTTTCCAAGTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGAT Celera SNP ID: hCV27486507Public SNP ID: rs3212219 SNP Chromosome Position: 158687039 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 13706 SNP Source:dbSNP; HGBASE Population(Allele, Count): Caucasian (C, 89|A, 27) SNPType: INTRON Context (SEQ ID NO: 255):GTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGATAACCTGGAAGCACTGCTACAACAGACGGCTGAGTMCCACCCCCAGAGTGTCTGATTCAGCAGGCATGAGGGCCTGAGAATATGCATTTCTAGAAAGTTTCCAGGGGAAGCAGATGCTGCTGGCGCTAAGACCACA Celera SNP ID: hCV27508808Public SNP ID: rs3212218 SNP Chromosome Position: 158687174 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 13841 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 81|A, 25)SNP Type: INTRON Context (SEQ ID NO: 256):GAATGGATAGCAAACGCACAGGCTCTGGAGTGGGAGCAAGCTTGGTGTGTTGAGGGATAGAAATACACAGAGCATGGCAAATACAGCAAGTGGTGTGAAAYGGGGTTGGAAAAGGTGGCGCAGGCCAGATCACTAGGACCAAGGAGTTTGAAATTTATTCCTAGTGCAGTATATCAGGTTGTATTTTTATCACTGGATAAT Celera SNP ID: hCV27883430Public SNP ID: rs4921493 SNP Chromosome Position: 158768685 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 95352 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (T, 64|C, 50)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 257):ATCCTCAGAAGTGGGCGGCAGAGAAGGAGGAACGTGCTTGAGTCGCAGTCCCCAAAAAGGGAGGAACTCATTGGCCCAGCTTAGGCCTGGTGTCTGCCTAYCTGTGGTTCAGTCAGCTGTGGTCGGTGGGCAGGACACACCTGAAGGAGCATATCTTGGCTGTGTGGGTTGGGCAGACATCCCACAATGCTCATGTAGGGG Celera SNP ID: hCV28024675Public SNP ID: rs4921230 SNP Chromosome Position: 158812974 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 139641 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 88|T, 30)SNP Type: DONOR SPLICE SITE; TRANSCRIPTION FACTOR BINDING SITE Context(SEQ ID NO: 258):GTGGTCTGAACGTTTATGTCTCCCTAAAATTCATATGTTGAATTCCTAACCCCCAAGGTGAGAGTGTTGGGAGGTGGAGCCTTTTAGTCTCCTGGCTGGGMTTAGTGGCCTGATAACATAGACTCCAGAGAGCTGGCTTATTCCTTCCACTATGTGAGGACACAGCAAGAAGCCGCTGTCTGTGGGGAAACAGAGGCTTAC Celera SNP ID: hCV29349404Public SNP ID: rs7704367 SNP Chromosome Position: 158754071 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 80738 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 75|C, 37) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 259):AGTTGGATTCCCCAAAATAATTAGTTAGTTAATTTGTTGACTGATTGATTGACACATTGCTAGCTCCTCTCAGACTGCCCAGTCTTCCTCATGCCCAAAGKGCTCTCATTCTGTTCATGATAACGCCCAAAATCTTTACCTTGGCACACTCGTTTCTCCATGATCTGCCCCTACTCCCTAATCGCTGTCACCTCCTACAAT Celera SNP ID: hCV29349406Public SNP ID: rs6556411 SNP Chromosome Position: 158715801 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 42468 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (G, 32|T, 88) SNPType: INTRON Context (SEQ ID NO: 260):CTCTTATTTTTAAGATGAGAAACTTAAAGCTTAGAGAAGGAATGTGACTTTCTGGATCAACATCTAGCAGTTGTTTATTTAGTGCTTACTACATAAAGAGMACTGGGCTAGAAGCAGTTGAGAGAGAAAAAAAGGGCTTACCTGGATCCCGCTTCCTAGGAGCAAATACTTTTACTCAATAAATATTTATTAAGTCAGTGT Celera SNP ID: hCV30449508Public SNP ID: rs3212220 SNP Chromosome Position: 158686773 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 13440 SNP Source:dbSNP; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (C,93|A, 27) SNP Type: INTRON Context (SEQ ID NO: 261):ATGTCACCAACAAGAGGCTACCCCCTGGGGAAACCTAACAGGAAAAAGGTAGTTGAGCCAGGAAAAGCCACCAGACCCTTTCTCTTGGCTTGAGGCATCAYATACATTTGAATAATAATCAAATTAACAATGTAATATGACTGTTTAGCAACAATGATGTGCTAATCATGGTTTTACATGGATTATCTTTAGTCATTAAAT Celera SNP ID: hCV31985570Public SNP ID: rs12651787 SNP Chromosome Position: 158772323 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 98990 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 64|C, 50) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 262):TAAATAAAATAAAATAAAGTAGAAAAGAAACAAAAATTATAAGATAGGGACATTAAATGGAGTTAGAAATGAGGCTAATAAATAATGAATATGCTGCACCRTGGAATACTACTCAGCCATAAAACAGAACAAAATAATGGACTTTGCAGCAACTTGGATGGAGCTGGAAGCCATTATCTTAAGTGAAATAATTCACAAATG Celera SNP ID: hCV31985582Public SNP ID: rs6556412 SNP Chromosome Position: 158719963 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 46630 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (G, 79|A, 39) SNPType: INTRON Context (SEQ ID NO: 263):CATTCTCATTTAAATTTGTATATCCCTGATTATTTTTGAGGCCAGGCACCTTCTCAGTCTATCAGTTATCTGTTAAGTTTTGAATCGATTTGTCCATTGGYTGTCTTACCTTATTGATTGGTAGAAGCCCTTAATTTTGGCATGAGCTCTTTATTAGTTACATGTGTGGCAAATATTTTCTCCCACTCAGGGACTTGCTGT Celera SNP ID: hCV30611467Public SNP ID: rs6869411 SNP Chromosome Position: 158714182 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 40849 SNP Source:dbSNP; HapMap; ABI_Val Population(Allele, Count): Caucasian (T, 71|C,49) SNP Type: INTRON Context (SEQ ID NO: 264):GTTATTTTTTCTTCTTACAAAAGTTGTTATTCAAGGATTATTAGCAGCCACCATTAATTAGGCACTTCATTATACTGTTTTACTTACCTCATACTCACCCRATTATTGAAGCAGGGATTCCTGCCCTAGGATTATAGGGATGGCCGACACTTGACACTTGACACTGAACAGATGAGATTGACAGCAGCTTGTCAGTCACAC Celera SNP ID: hCV30017148Public SNP ID: rs9313808 SNP Chromosome Position: 158753422 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 80089 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 22|G, 98) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 265):AAAGAACGTTATTGATGGAAATTTAGGGGTGTTTGGGGAATATTACTAAAATTTGTGTGTAACCAAATTTGTGACCTTCTAACAAATGTCCCCCTGTAGASCTGTGAGAAACAATATTAGGGTTGACCCACTCAGTTCATGCTTTTTTTTTTTTCTGTTAAAAAAAGCCAGCATTTCAAGCAGTGAGTAGACCAGTAAGCT Celera SNP ID: hCV32389145Public SNP ID: rs4921504 SNP Chromosome Position: 158840941 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 167608 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (C, 89|G, 31)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 266):ATAGCTTTTCATTTTTTAACTGGGGCCAAAGTTAGTTAATCCACAAGAATGGGGATCCCAGCTGTCATTTTGGTTGATATCACAACTGACGACCAAGACCRTCACAAATATGGGAGCAAGTCTGATTTGTAACATTATTATAATTATGAATCCAATTACTTTAAGGAATGCACGAAAGGCTTTTTAAAAATTTCAATAGTA Celera SNP ID: hDV71045748Public SNP ID: rs6894567 SNP Chromosome Position: 158689546 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 16213 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 94|G, 26) SNPType: INTRON Context (SEQ ID NO: 267):ACAGACCTAGTTAGACCATAGTCCATATTTCAAATATAATTACATGTGCTCATAGCTGAGAACCTTCTCCTGGGATGGATGCATTTCACCAGGTCACTGCYGAAATGTTGTACTTTTATGGATGGTGATGAGGAAGCATCTGTTTTAGGTGTGGTATTTCCTGGAGGCAGAAAACTGCTTGAGTTAGCTCATTCAGTTTTT Celera SNP ID: hCV31985592Public SNP ID: rs7709212 SNP Chromosome Position: 158696755 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 23422 SNP Source:dbSNP; HapMap; ABI_Val Population(Allele, Count): Caucasian (T, 76|C,44) SNP Type: INTRON Context (SEQ ID NO: 268):AAAACATATGGGTTGGGTTATCCACTTCAATGACTGCACATTAAGCAAGAGTATAGTGTACCATGTTTTATTTAACCATTCCTCTGCTGATTATGTCTTTWTGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAATGGTAAAGTCA Celera SNP ID: hDV75439995Public SNP ID: rs3213097 SNP Chromosome Position: 158681257 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 7924 SNP Source:CDX; dbSNP Population(Allele, Count): Caucasian (T, 89|A, 27) SNP Type:INTRON Context (SEQ ID NO: 269):GTGATTCAGATCTGGGATGGGGCTCAGGAACCTGCATTTTAACAATGGAGGTTCTAATGTGGTCATTGGCAGGTTGTTCTAATGTGGGGGCCACATTAGA GC/TTAGACCTCTCTCGGAGACAGGCTGTACATGGCCAGCCAGCATTCTGGTAATATGAGCCAAATGCCCATTGACCTAATTTTGGAGAAGAGGTTTATCAACATGTC Celera SNP ID: hDV79877074Public SNP ID: rs17860508 SNP Chromosome Position: 158692783 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 19450 SNP Source:dbSNP Population(Allele, Count): no_pop (GC, —|TTAGA, —) SNP Type:INTRONIC INDEL Context (SEQ ID NO: 270):TTATCAATTCTTCATTTCATGGATTGTGTCTTTGGTGTTATATCTAAAAAGTCATCACCAAACGCTAGATCATCTAGATTTTATTCTATGTTATGATCTARGAGTTTTATAGGTTCACATTTTATATTTAGGTCTGTGAATTAGTTTTTGTGAAAACTGTAAGGTCTGTGTCTAGTTGATGTTCAGTTATTCTAATATCAT Celera SNP ID: hCV7538744Public SNP ID: rs1422880 SNP Chromosome Position: 158748197 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 74864 RelatedInterrogated SNP: hCV11314640 (Power = .51) SNP Source: dbSNP; Celera;HapMap; HGBASE Population(Allele, Count): Caucasian (G, 112|A, 8) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 271):TAATACATATAATACAGAAAATATCTGTTAATTGGCTATACTATTCATAAGGCTTCCAGTCAATAGAAGGCTGTTATTAGTTAAGTTCTGGCTGAGTCAARAGTGATACATAAATTTTCAACTGCATGGTGGGGTCAACATTACTAAACCCCTCACCCTTCATGGGTGAACTGTATTTTTATATCTATATCTAATCTATAT Celera SNP ID: hCV7538751Public SNP ID: rs1422879 SNP Chromosome Position: 158751276 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 77943 RelatedInterrogated SNP: hCV11314640 (Power = .51) SNP Source: dbSNP; Celera;HapMap; HGBASE Population(Allele, Count): Caucasian (A, 111|G, 7) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 272):ACTGAGGACAAACTAGGGAGTGGTGGGGACCACAGTGAACCCATGGCGCATGCTCTTTCCCAGAGGCAGGTCGCTCCTCAGATCCAGCTGACTGTGCCAGMTGTGAAAGCAAGATGGGCATCACAGTTCTTGTGATGTTTAGAGAAGAGCTGGAAAACTGAACTTAAATGTGAAGTAGCTATTTTAAAGGCTGGCCACAAT Celera SNP ID: hCV7538752Public SNP ID: rs1363669 SNP Chromosome Position: 158754724 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 81391 RelatedInterrogated SNP: hCV11314640 (Power = .51) SNP Source: dbSNP; Celera;HapMap; HGBASE Population(Allele, Count): Caucasian (A, 111|C, 7) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 273):AATATCTGATTGTGTTACTTCCTTGCTGAAAACCCTTCAGTGGGTTTCAGGGCCCGGGGCCCCCAGAACAAGATTCTGAGTCCTGCAAGCTTGCAAGTCCKCCATGCTCTGCCTCCTGGCTACCTCTCTCTTTTCTTTGCCTTTCTCTTTAGGAGGCCAGAACCCCGGTCTGTTTTCTTTCCTGCAATATCCCTGTGGCCA Celera SNP ID: hCV15824051Public SNP ID: rs2853697 SNP Chromosome Position: 158675981 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 2648 RelatedInterrogated SNP: hCV15894459 (Power = .51) Related Interrogated SNP:hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap; HGBASEPopulation(Allele, Count): Caucasian (T, 102|G, 18) SNP Type:TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 274):TGGAGGTTAACATCAATTAACATCAATAAGAGACTTGATGTTAATTCATTACACTCACCATGACTTGGCTTTTCAATTTGTTGTTGTTGTTGTTTTTAACYCTTATGAGCGAAAGAGAAAATTGATACTATCCAAGGGTATAGAATTACCTTTCTGGTCCTTTAAAATATCAGTGGACCAAATTCCATCTTCCTTTTTGTG Celera SNP ID: hCV15879826Public SNP ID: rs2288831 SNP Chromosome Position: 158682591 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 9258 RelatedInterrogated SNP: hCV2084270 (Power = .51) Related Interrogated SNP:hCV2084293 (Power = .51) Related Interrogated SNP: hDV71045748 (Power= .51) SNP Source: dbSNP; HapMap; ABI_Val; HGBASE Population(Allele,Count): Caucasian (T, 91|C, 25) SNP Type: TRANSCRIPTION FACTOR BINDINGSITE; INTRON Context (SEQ ID NO: 275):TGAAGCAGTCCAGTAGAGCTTAGTCTTCCCATTTAATGAAGAAGCGTACTGAGGCCAACGATCTAAGCATGGTCACAGCAAGTCAGAAGTACAAGGGCTAYAGCTCAGACCTTTTGTCTCTTGGGCTTTGCAAGGGATGCCTAATGCTAGTGTCTAAACTGGCCTTTGAGGAATGGCTTAGTATAGTATTTCAGAGTGTGT Celera SNP ID: hCV16044033Public SNP ID: rs2569254 SNP Chromosome Position: 158683827 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 10494 RelatedInterrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap;HGBASE Population(Allele, Count): Caucasian (C, 102|T, 18) SNP Type:INTRON Context (SEQ ID NO: 276):AGAGTTCTAATTCACTAAACAAAACCTCAGTATACACCAAAATAGAACCTCCTTAAAGCATAAATCTCACATGCCCTGCAAAACAGTAACGCAATGAAAARAACAAAGTATCTAGGCAACAACTAACATGATGAATAGAACAGCACCTCACATCTCCATATTAACTTTGAATGTAAATGGCCCAAATGCTCCACTTGAGAG Celera SNP ID: hCV27106364Public SNP ID: rs4262088 SNP Chromosome Position: 158738822 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 65489 RelatedInterrogated SNP: hCV11314640 (Power = .51) SNP Source: dbSNP; Celera;HapMap Population(Allele, Count): Caucasian (A, 112|G, 8) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 277):TTATGTCTTTATGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAAWGGTAAAGTCAGGATGATCACCTGGGGTTTGCTTCGGTGATGATTAAAGTAAGCCACATGGGGGTTAACACATAGGTCTTGTATTTATGGAAGTTGCTTTC Celera SNP ID: hCV32389155Public SNP ID: SNP Chromosome Position: 158681347 SNP in GenomicSequence: SEQ ID NO: 18 SNP Position Genomic: 8014 SNP Source: HGBASE;dbSNP Population(Allele, Count): no_pop (A, —|T, —) SNP Type: INTRONContext (SEQ ID NO: 278):TACCTCCCAACAGTCCTGTGAATTTACTATGCTACCCCAGGGTGACCTGGTAGAGAGTTTGGAACCACAGCTAGCCATAGTACTTTCAAACTACTAAAGTYAGATATCTCTTTGCCACCAAATCCCTCCTCAGGGCCATATGTGACCCTGCATTTTGTGCAGGGATTCCAGGAAGCAAAGTTGTCACTCTTTCTGGAAACT Celera SNP ID: hCV31985590Public SNP ID: rs11738529 SNP Chromosome Position: 158702844 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 29511 RelatedInterrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (T, 64|C, 46) SNP Type: INTRONContext (SEQ ID NO: 279):AGTGACAATTACATATCAGGCACCCAGCTAAATTCTGTGAATGTAGTAAGCAGATCAGACCTGGACTCTGTCCTCATAGAGCTAAATAGATATGTGCAGARGACAAAATGCTATGAAGGAAATGAATGGGTGGTGAGACAGAGAATCACAGGGGAGGGCTCTCTGATGAGGTGGCATTTAAGTTGGGACCTACAGGTGAAC Celera SNP ID: hDV70836316Public SNP ID: rs17056705 SNP Chromosome Position: 158701831 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 28498 RelatedInterrogated SNP: hCV11314640 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (G, 112|A, 8) SNP Type: INTRONContext (SEQ ID NO: 280):CCTGCCAGAAGGCAATTAAAGAGTGGAAGAGCAGAAATGCAGAGAAGGAATTCAACACCTGCTCCACCAGCACGTTCCTTGGTCGCTCTCGTCTGTTTCCYTAGCTGGATCACATTCTTGGTGAATGAGAGAAAGTATGAGGATTAATGAGCAGACCTGTCTTTGGGATACCCTAGAACCATGATGCAATGCAAATATCAC Celera SNP ID: hDV70836317Public SNP ID: rs17056706 SNP Chromosome Position: 158703333 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 30000 RelatedInterrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (C, 69|T, 49) SNP Type: INTRONContext (SEQ ID NO: 281):GGATGAGTCTCACTTAGTCATGAAATGCAGTCTCTTTGTATGTTGCTGGATTTAGTTTGCTAGTACTTTGTTGAGAATTTGTGCCTCCATATTCTTAAGTRATTTTGGTCTGCAGTTTTTTTTTTGAGATGTGTTTGTCTGGTTTTGATATCAGGGTAATACTAATTTCATAGAATAAGTTAAGAAGTGTTTCCTCCTCTT Celera SNP ID: hCV31985588Public SNP ID: rs6878967 SNP Chromosome Position: 158711610 SNP inGenomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 38277 RelatedInterrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP; HapMap;ABI_Val Population(Allele, Count): Caucasian (A, 71|G, 49) SNP Type:INTRON Gene Number: 7 Gene Symbol: Chr1: 67490910..67543062 Gene Name:Chromosome: 1 OMIM NUMBER: OMIM Information: Genomic Sequence (SEQ IDNO: 19): SNP Information Context (SEQ ID NO: 282):TCTGGCAAAGAGAAGGCCACACACCAGGAAGCCCCTGAGGGTACAGGGACATTACTGATTATAAAGGAGGGAAGGAACAAGCTATGTGTGTTCCTGATAAMCCCTGGCCCTCGGGATTGGCTGTCAAGGGGCTCAAAACCCAGTCCAAGGGACAAACACATCATCCAAGCCTTGCAATGCAGTGATGTAAGTGCAATGATA Celera SNP ID: hCV261080Public SNP ID: rs10889675 SNP Chromosome Position: 67494804 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 3894 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (C,105|A, 15) SNP Type: INTRON Context (SEQ ID NO: 283):CAGTGGAAATAAATATTTGATGTTATTTTCAATAAATTGTTACTGGAGTTAAACCTCTTGCTATCCTGACAATTCCTCCCTACATCACCCTCTTTGCAATRGCAGATGGAAGAATTGGCAATAAATGCAATTCAGCTTGAAGAAAACACCCTAAATATTAGAAACCTGTGAAGAACCACCGGATTGCCTTATCAACTCATT Celera SNP ID: hCV2720238Public SNP ID: rs11209032 SNP Chromosome Position: 67512680 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 21770 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 83|A, 37)SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 284):GACTAGAAATTGAGGCTATACCTGCAATGGGAGCAATGTACCTGCCTTTGTCCCAACTCAGGGGAAAAATTCAAGCTGCTTTATCACAATGCAAACTTCGYGGGGGAGAAAGGGTTTCTTTCTATAATTCTTGTATTCAAGAAGGATTCATTGAACTACTGAATGTCCTTACTGTTATATGTGCAAGGCCATTTGAAGGAT Celera SNP ID: hCV2720250Public SNP ID: rs4655531 SNP Chromosome Position: 67500366 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 9456 SNP Source:Celera; HGBASE; dbSNP Population(Allele, Count): no_pop (C, —|T, —) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 285):GTGCAATCTCGGCTCACTGCAACCTCCATCTCCTGGGTTCAAGTGATTCTCATGCCTCAGCCTCCCAAGTAGCTAGGAATACAGGCACACACCACCATTTSCAACTAATTTTTATATTTTTGGTGGAGACGGGATTTCACCATGTTGGCCAGGCTGCTCTTGAGCTCTTGGCCTCAAGTGATCTGCCTGTCTTTGCCTCCC Celera SNP ID: hCV8367042Public SNP ID: rs1008193 SNP Chromosome Position: 67492499 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 1589 SNP Source:dbSNP; Celera; HapMap; HGBASE Population(Allele, Count): Caucasian (G,82|C, 38) SNP Type: INTRON Context (SEQ ID NO: 286):TTGAGTATTTCTAAGCTGCTCGATAGATTAGAGTTGTTTGGTGTGGCAGTTCCCCAGTGTGTCCAGTTGCTCACAAATTTTGACTTGAATGTTCTTTGCCRAATTGGCACTGAGTTTCTCCTTCTTGCCATCATTTGCTTCATGAAATAATCTTTCTTTCGTTTACATTTATAATCAAGTGCAGTAGAAAGATTTTAAATG Celera SNP ID: hCV8367043 PublicSNP ID: rs1343151 SNP Chromosome Position: 67491717 SNP in GenomicSequence: SEQ ID NO: 19 SNP Position Genomic: 807 SNP Source: dbSNP;Celera; HapMap; ABI_Val; HGBASE Population(Allele, Count): Caucasian (G,73|A, 47) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON Context(SEQ ID NO: 287):ATCTTGTTTCCAGAGTAGTGACATTTCTGTGCTCCTACCATCACCATGTAAGAATTCCCGGGAGCTCCATGCCTTTTTAATTTTAGCCATTCTTCTGCCTMATTTCTTAAAATTAGAGAATTAAGGTCCCGAAGGTGGAACATGCTTCATGGTCACACATACAGGCACAAAAACAGCATTATGTGGACGCCTCATGTATTT Celera SNP ID: hCV11283764Public SNP ID: rs10889677 SNP Chromosome Position: 67497708 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 6798 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (C, 87|A, 33)SNP Type: UTR3 Context (SEQ ID NO: 288):GACCTTGAACTCCAGGGCTCAAATAATCTGCCCACCTTGGCCTCCCAAAGTGCTAGGATTACAGGCATGAGCCAATATGCCCAGCCAAATATCTTAATCAMCATCATCATCATCATCATAAACTGCCGGTAGGAAGTTTGGCATAATGTGTCACATCAATTATAAATCACAGATGATTTTACTTGATATAGTTAGCTAGAG Celera SNP ID: hCV26465573Public SNP ID: rs11209030 SNP Chromosome Position: 67510363 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 19453 SNP Source:dbSNP; Celera; HapMap; ABI_Val Population(Allele, Count): Caucasian (C,79|A, 41) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 289):CAGCCTAAATTTTAGGGCTTTATTATATAACATTCTCTTTTTAAATATGCGGTAGTTACGGTCACCTTGGAAAGTTCTACAAAATATCCCTTAAGTTTTTYGAACTTTCCCACATGGGAATCTTCTGGTTATGAGAGTTTGCTCTATTTAATATGTGTACGGTTTCACTGCTAGGGTGGTTCTCCCACTTATCTTGAATCT Celera SNP ID: hCV30243123Public SNP ID: rs6693831 SNP Chromosome Position: 67493455 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 2545 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (T, 30|C, 90) SNPType: INTRON Context (SEQ ID NO: 290):GGTTGAAGTATGGTCCACTGGGATTGGCCAAGACTCAGTTACTGTTACAGGCACATACTCCTAAGTCAGGTTTTCACTCTTGTCTGCCTGTTAAGTTAGGWTACAGTTCATCCACAGGGATTCAAATATAGAGGTATGAAGTCCTTCTCAGGCCATATTTAGTTTGCTTTAACACTTGAATTCCACCCAAACAAATCAGCT Celera SNP ID: hCV31222811Public SNP ID: rs12085634 SNP Chromosome Position: 67491301 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 391 SNP Source:dbSNP Population(Allele, Count): no pop (A, —|T, —) SNP Type: INTRONContext (SEQ ID NO: 291):AATTAGGCCTGCGAAAGAGACAGACTCCTTCCAGTGACAGAGTGTTAGGTGGCAAGTTCAGAAGCTGTCAGTCTTGTTTTTCTCCATGTGGCCAGAATGAMAGGAAGATGGCCCATAGACGCAGAATAAGAAGAATAATAAACAGATCCACAGAAAAGGACAGAGGAGAGATGAAATGAGAACCCTGAATGCATTAGAATC Celera SNP ID: hCV31222784Public SNP ID: rs11209031 SNP Chromosome Position: 67512176 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 21266 SNP Source:dbSNP; HapMap Population(Allele, Count): Caucasian (A, 76|C, 40) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 292):GAGGAGTTGCCATCTATTAATACTTATTTTCCACAAAATATTTTGGAAAGCCACTTCAATAGGATTTCACTCTTGGAAAAGTAGAGCTGTGTGGTCAAAAKCAATATGAGAAAGCTGCCTTGCAATCTGAACTTGGGTTTTCCCTGCAATAGAAATTGAATTCTGCCTCTTTTTGAAAAAAATGTATTCACATACAAATCT Celera SNP ID: hCV31222798Public SNP ID: rs11465827 SNP Chromosome Position: 67497416 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 6506 SNP Source:dbSNP Population(Allele, Count): Caucasian (T, 117|G, 3) SNP Type:MICRORNA; UTR3 Context (SEQ ID NO: 293):GGCCTCCCCAGCCATATGGAACTGTAAGTCCATTAAATCTCTTTTTTTTGCAAATTGCCCAGTCTTGGGTATGTCTTTACCAGCAGCGTGAAAATGGACTWATACAGCATTTACCACAGTGTCTGGCTCATAGTAACTGTGGCAGAGCCTGCTAATTGTCCGTTCAACTTCCGTTCTCAAATTCTTACTTCCTAACAGAAC Celera SNP ID: hCV31222786Public SNP ID: rs1857292 SNP Chromosome Position: 67510910 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 20000 SNP Source:dbSNP; HapMap; HGBASE Population(Allele, Count): Caucasian (T, 10|A,106) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 294):TAGAAGTGGCTCTGTTTCAAGCTCTGGTAAGCCTATTAGCTAACTCTTTCCCCAACCTCATGTCATCTGAACAAAGGGTTTCTAGGCTAAAAATAAAATAMTTTTTAAAAGTTCAAAAACAACTGGTCAACAGAATAGAGTCTGAGTTCTGTAACACAAGACTTCTGTGATCTGATCCACTCACCATTCCAGCTTTACTCC Celera SNP ID: hCV261079Public SNP ID: rs10889676 SNP Chromosome Position: 67495155 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 4245 RelatedInterrogated SNP: hCV11283764 (Power = .51) Related Interrogated SNP:hCV1272302 (Power = .51) SNP Source: Celera; dbSNP Population(Allele,Count): no_pop (A, —|C, —) SNP Type: INTRON Context (SEQ ID NO: 295):ACATTTTTTTTCAATTTCATGGAAAAGAGGTTTTTCATTTTTCCAAAAATTGTACCAAGGTAAAGCAAAGTTCTAGTTGATGCAGGTGCATTGTATAGGCRTTAGCAATACTGCCCTCATTATGCACTCATTAGACAGTAGTGCAACCCCAAGAAAAGGATGGTTAGATATTTCTTTATAGCAATGCAAGAACAGCCTAAC Celera SNP ID: hCV2720226Public SNP ID: rs2863209 SNP Chromosome Position: 67505934 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 15024 RelatedInterrogated SNP: hCV31222786 (Power = .51) SNP Source: dbSNP; Celera;HGBASE Population(Allele, Count): Caucasian (G, 12|A, 106) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 296):TTTATAAACAGCTAATCGGAACCTCTATTTGTCATAGGCTTTTGAGTTTATTGTTGGGACCCATAATAGGACCATTTTTTCTTTTTGTCTTCAAAATTATYGTAGGCCAGGTGCAGTGGCTTACACCTGTAATCCCAGCACTTCGGGAGGCTGAGGCGGGTGGATCAAGTGAGGTCAGGAGTTCAAAACCAGCCTGGCCAA Celera SNP ID: hCV2720231Public SNP ID: rs11209034 SNP Chromosome Position: 67517272 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 26362 RelatedInterrogated SNP: hCV2720238 (Power = .51) SNP Source: dbSNP; CeleraPopulation(Allele, Count): Caucasian (T, 37|C, 83) SNP Type: INTERGENIC;UNKNOWN Context (SEQ ID NO: 297):AGCCAGTTAATGTCTTTAACAATAAGTGTTAAGGAGCAGCTGCTGCACTTGGATAACAAGTAATTCAAGGCGCCCACTTAACAGAAATGTTAAACTATAASAAGAACCATCTGAGGATTAACAGAAACTTTTTTTTTGTAGATTTCAAGGGAACTTGCCTTTCAGAATAATAGTACCTAAAGTATTTATAAACAGCTAATC Celera SNP ID: hCV2720233Public SNP ID: rs11209033 SNP Chromosome Position: 67517088 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 26178 RelatedInterrogated SNP: hCV2720238 (Power = .51) SNP Source: dbSNP; Celera;HapMap; ABI_Val Population(Allele, Count): Caucasian (C, 83|G, 37) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 298):ATTGAAAAGAAGCAGAGCAATAGAGATGAGAGGAAAATCTGAAAAGATAATGACACAATTTCCCACTTAATTTTCATTAAGTAAGAGATGAAAACTTTAGMCTCGGCATCAGGAAGTTTGATTTCTTTAATTAATTTTTTTTTTGAGTCAGGGTCTCACTCTGTTGCCCAGAGTGAGTGCAGTGGCATGGTCACAGCTCAC Celera SNP ID: hCV2720251 PublicSNP ID: rs11465817 SNP Chromosome Position: 67493685 SNP in GenomicSequence: SEQ ID NO: 19 SNP Position Genomic: 2775 Related InterrogatedSNP: hCV11283764 (Power = .51) SNP Source: dbSNP; Celera; HapMapPopulation(Allele, Count): Caucasian (C, 66|A, 42) SNP Type: INTRONContext (SEQ ID NO: 299):AGTCCTGGAAAAACAAGACAGCCTCAGCTCAGTAGTTCCCATACAAATTCCAATGTTTAGATTGTTTGGCATAACTGGAGTCACATGCTTATCCATGAACYAAATAATCATCGTTGACAGGAAATATGGTATTCTCATTGGCCAGGTCAAGTCACATGCTCACCAGAGGGGTGATGGGGAACTAGCTCCACTCTTGCGCGT Celera SNP ID: hCV3277187Public SNP ID: rs7546245 SNP Chromosome Position: 67523062 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 32152 RelatedInterrogated SNP: hCV2720238 (Power = .51) SNP Source: dbSNP; CeleraPopulation(Allele, Count): Caucasian (T, 84|C, 36) SNP Type: INTERGENIC;UNKNOWN Context (SEQ ID NO: 300):GAATGGCCTAGGAAAGTTACATTCCAGAAGGAAACATGTTATTACACATAGGAATCGATTGGTCCTCCATGAGTACCTACAATTGAATTCTATGTATTAAMACCGCAGAAAAACACATACAGATAGAAAATATTTTTAATCAAGGACTAGTATCCAAAGCAAAACAAAGTGGAAATTTGGTAATTATCCTGTGAATTTCTG Celera SNP ID: hCV3277191Public SNP ID: rs12119179 SNP Chromosome Position: 67520003 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 29093 RelatedInterrogated SNP: hCV2720238 (Power = .51) SNP Source: dbSNP; CeleraPopulation(Allele, Count): Caucasian (A, 83|C, 37) SNP Type: INTERGENIC;UNKNOWN Context (SEQ ID NO: 301):AACGACTCTTGGTGTCTTCCAGCGCTAATGATTTATAATTAAGTTAGATTTGTAACCTTAAAATACTTTATAGCATTTACCCTGCTTGTGAGTGTGTATASATTTAACAGAATTCAACAAGCACGTGCTGAGAAAATTCTTTACCCAGGGCATTCAGCTACCTACAGTATAGTCAGAGGGAAATAAAACATGGTTTGGAAT Celera SNP ID: hCV3277193Public SNP ID: rs12141431 SNP Chromosome Position: 67519611 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 28701 SNP Source:dbSNP; Celera Population(Allele, Count): Caucasian (G, 84|C, 36) SNPType: INTERGENIC; UNKNOWN Context (SEQ ID NO: 302):GCTCATGCTTATGAAATTCACTGGTCTTACCATGTTCCCCATCATCCTGAAGAAGCTGGATTGATATAATGGTGGAATGGCCTATTGAAGTCACAATTACWGTGCCAACTAGATGACAATACTTTGCAGGGCTGGGACAAAGTTCTCCAGAAGGCCGGGTATGCTCTGAATCAGTGTCCAATATGTTACTGTTTCTCCCAA Celera SNP ID: hCV11283811Public SNP ID: rs4655536 SNP Chromosome Position: 67530442 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 39532 RelatedInterrogated SNP: hCV31222786 (Power = .51) SNP Source: dbSNP; CeleraPopulation(Allele, Count): Caucasian (T, 108|A, 12) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 303):GTAATCTATCACACATGAAAAAAGCTTTTATCAAGCTTAAAGGATTACAGCATTGTTTGATCTTCTGCAAATGTTTCCACTGCAGCGAGTGCCTCCTTTTYGCCCCCTAGAGTGGGAAGGAAGCTGCTTTCTCATTCTGTGGTGTCTTAACCCACATCACTATTCAGCACAAAGGAGACACTTCTGATTCTGTCTTTGCCA Celera SNP ID: hCV11728628Public SNP ID: rs2000252 SNP Chromosome Position: 67500143 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 9233 RelatedInterrogated SNP: hCV8367042 (Power = .51) SNP Source: Celera; HGBASE;HapMap; dbSNP Population(Allele, Count): no_pop (C, —|T, —) SNP Type:INTERGENIC; UNKNOWN Context (SEQ ID NO: 304):ACTGCAAATCATCTAAGAAGAGAAAAACCCCTCTGAATTACATGACTGAGTTTCAGAATGTGAGTAAAGTATGGCTAACCAAAATGTTCAAGCAAACTGAWGCAAATTTCCTTTTCTATGACTGTGTAAGCAAAACTCTTTTGCACGATACTAAGTTTGATGTGGTGTAGCATGTAAAAGAGAAAGCACCTTTATCTGTGT Celera SNP ID: hCV29129920Public SNP ID: rs6677188 SNP Chromosome Position: 67512991 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 22081 RelatedInterrogated SNP: hCV26465573 (Power = .51) Related Interrogated SNP:hCV31222784 (Power = .51) SNP Source: dbSNP Population(Allele, Count):Caucasian (T, 80|A, 40) SNP Type: INTERGENIC; UNKNOWN Context (SEQ IDNO: 305): TTTGCAATTCTAGAATCGGACAACACCTCATACTATAAAACAGAGTGAGTGTTCTGATGAGCTGAGCAGAGGAGGTTGATTTAAGGAACTTTCTTATCACRCTGGCGAAAACTGGCCTGTTTAGGGATTTGGCTGTTATCTCTGTGTCCTGATTTGTTGAAAGGTCAGATAAAGATCTTAGTTTCAGCAGGTTAGTGTGGA Celera SNP ID: hCV30423493Public SNP ID: rs7539328 SNP Chromosome Position: 67505191 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 14281 RelatedInterrogated SNP: hCV31222784 (Power = .51) SNP Source: dbSNP; HapMapPopulation(Allele, Count): Caucasian (G, 76|A, 42) SNP Type: INTERGENIC;UNKNOWN Context (SEQ ID NO: 306):TCTCTTTTTTTTGCAAATTGCCCAGTCTTGGGTATGTCTTTACCAGCAGCGTGAAAATGGACTTATACAGCATTTACCACAGTGTCTGGCTCATAGTAACWGTGGCAGAGCCTGCTAATTGTCCGTTCAACTTCCGTTCTCAAATTCTTACTTCCTAACAGAACCCCTATGTCATTGATGATAGCAGTTCTCTCAGTGAAA Celera SNP ID: hCV31222785Public SNP ID: rs12045232 SNP Chromosome Position: 67510947 SNP inGenomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 20037 RelatedInterrogated SNP: hCV26465573 (Power = .51) Related Interrogated SNP:hCV31222784 (Power = .51) SNP Source: dbSNP; HapMap Population(Allele,Count): Caucasian (T, 80|A, 40) SNP Type: INTERGENIC; UNKNOWN GeneNumber: 8 Gene Symbol: Chr5: 158452593..158472593 Gene Name: Chromosome:5 OMIM NUMBER: OMIM Information: Genomic Sequence (SEQ ID NO: 20): SNPInformation Context (SEQ ID NO: 307):ATTTCCTTTGGCTGTGCAGAGGCAGCACATACCTCACCTGGGGTGGTGAGTGTGCTTTATTTTAATCAAGCCGAGTGTATTCATAGCTTTTCTTCTTGGTRTCCTTGTGCTTTCAGTCTGGCTTTCTCATCCTGTAATAAATGTTTAAGTAGGAAGGAGGCTAAAGAGAAGGTGGAAGAGAGACAGAGTGAGTGACAGAAA Celera SNP ID: hCV1992722Public SNP ID: rs7732511 SNP Chromosome Position: 158462593 SNP inGenomic Sequence: SEQ ID NO: 20 SNP Position Genomic: 10000 SNP Source:dbSNP; Celera; HapMap Population(Allele, Count): Caucasian (G, 101|A,19) SNP Type: INTRON

TABLE 3 Primer 1 Primer 2 Marker Alleles (Allele-Specific Primer)(Allele-Specific Primer) Common Primer hCV11264637 A/GCCAAAACCAGACAAGGACAT CCAAAACCAGACAAGGACAC (SEQ GCTGCAATGCCTGGTGAGTATTAT(SEQ ID NO: 308) ID NO: 309) (SEQ ID NO: 310) hCV11269323 A/GGGGTTGTCCATGACCTCTA (SEQ GGTTGTCCATGACCTCTG (SEQ IDCCACTGAGCGGGTAAACACTTAG ID NO: 311) NO: 312) (SEQ ID NO: 313)hCV11283754 A/G GGGCACTCTGAATTATCAATCAAT GGCACTCTGAATTATCAATCAATTGTCAAGGTGTAGGTAGGTCTGTGTA TA (SEQ ID NO: 314) (SEQ ID NO: 315) (SEQ IDNO: 316) hCV11283764 A/C AATTTTAGCCATTCTTCTGCCTA TTTTAGCCATTCTTCTGCCTC(SEQ AAATACATGAGGCGTCCACATAATG (SEQ ID NO: 317) ID NO: 318) C (SEQ IDNO: 319) hCV11314640 C/T GGCCCTGACTGATTTCATG (SEQ TGGCCCTGACTGATTTCATA(SEQ ID GGTGGCCTCAGCTTCCTT (SEQ ID ID NO: 320) NO: 321) NO: 322)hCV1272298 A/G TGCAAAAACCTACCCAGTTT (SEQ TGCAAAAACCTACCCAGTTC (SEQ IDTTCATTAGACAACAGAGGAGACAT ID NO: 323) NO: 324) (SEQ ID NO: 325)hCV1272302 A/G TAATAGGAAACTAATATAGAAGAT TAGGAAACTAATATAGAAGATGATGAATGTTTGCCAAGTTGGTCTTGAACT GATGACT (SEQ ID NO: 326) CC (SEQ ID NO: 327)(SEQ ID NO: 328) hCV15803290 A/G CTCTCCCTGGGGATGAA (SEQ IDCTCTCCCTGGGGATGAG (SEQ ID CAATTGACTGTAACTGCTCCAAGAC NO: 329) NO: 330) A(SEQ ID NO: 331) hCV15894459 A/G ATTGCCTTTCCCAACAAGT (SEQTGCCTTTCCCAACAAGC (SEQ ID AATTTTGGTCCCACCGCTCATT ID NO: 332) NO: 333)(SEQ ID NO: 334) hCV1992693 A/G CGGCCATGGTTCTAAGAAA (SEQCGGCCATGGTTCTAAGAAG (SEQ ID GAAATGTGGGCTGAGGGATAG ID NO: 335) NO: 336)(SEQ ID NO: 337) hCV1994965 A/G TTACTTCCTACATTTACAACCTAGACTTCCTACATTTACAACCTAGAAC GAGGAGACCTCAAAGCAGAACCTT AAT (SEQ ID NO: 338)(SEQ ID NO: 339) A (SEQ ID NO: 340) hCV1994966 C/TCTCCTTAAGAAGAGAGATCAACA CTCCTTAAGAAGAGAGATCAACAAATGGTCTCAATCTCCTGACCTTGTG AG (SEQ ID NO: 341) (SEQ ID NO: 342) (SEQ IDNO: 343) hCV1994967 C/G CTGGGAATCAGATGATTGAGC CTGGGAATCAGATGATTGAGG (SEQGTGTAAATCTGCCAATTAGCCATCT (SEQ ID NO: 344) ID NO: 345) CT (SEQ ID NO:346) hCV1994973 A/G GCTCTACCTTTATGCACTGTTTTA CTCTACCTTTATGCACTGTTTTGGTCACAATGAAATACTAGTCAGGAC (SEQ ID NO: 347) (SEQ ID NO: 348) TCTCA (SEQID NO: 349) hCV1994974 C/T GCAGTGGAGTTATTAGAAGTTATTGCAGTGGAGTTATTAGAAGTTATTTA GTGCCCTGTGGGGTTAAACA (SEQ TAGATG (SEQ ID NO:350) GATA (SEQ ID NO: 351) ID NO: 352) hCV1994990 C/GGATGCAACTTTAGAGGCATTTG GATGCAACTTTAGAGGCATTTC (SEQTTAGGACTGGAAACCACGAAGTCA (SEQ ID NO: 353) ID NO: 354) A (SEQ ID NO: 355)hCV1994992 C/G GATCAAAGATGTAAATCCAGACTA GATCAAAGATGTAAATCCAGACTATTCCTCTGTGTTCACACTGATATCAAT TTG (SEQ ID NO: 356) C (SEQ ID NO: 357) ACCT(SEQ ID NO: 358) hCV1995017 C/T TGGCAGCCTCATAATATTTCAACTGGCAGCCTCATAATATTTCAAT CAAAGGAACTCCTCTTGTGACATCT (SEQ ID NO: 359) (SEQID NO: 360) (SEQ ID NO: 361) hCV2081970 C/T AATTAACTTTAGAATCAGACTTGAAAATTAACTTTAGAATCAGACTTGAT CAGCCCAGGAGTTGGACAAG (SEQ TACAG (SEQ ID NO:362) ACAA (SEQ ID NO: 363) ID NO: 364) hCV2081982 A/GTTCGATCAGGCAGTAGGATAT TCGATCAGGCAGTAGGATAC (SEQCATTTTGTTGGTTACTAACAGCACT (SEQ ID NO: 365) ID NO: 366) GAA (SEQ ID NO:367) hCV2084270 A/G CAACCAAGAAATAGTCATTTACAG CAACCAAGAAATAGTCATTTACAGAGATCAGGAGCTGGAGGAAACTTCT AA (SEQ ID NO: 368) (SEQ ID NO: 369) (SEQ ID NO:370) hCV2084281 C/T GGGGTGCTGTGTTTCTTTC (SEQ GGGGTGCTGTGTTTCTTTT (SEQ IDCTAACAGCTGTAATGAGGTATAGTT ID NO: 371) NO: 372) CACATACTC (SEQ ID NO:373) hCV2084293 G/T CAATGAGCATTTAGCATCG (SEQ TTCAATGAGCATTTAGCATCT (SEQTGGAGGAAAAGTGGAAGATATTA ID NO: 374) ID NO: 375) (SEQ ID NO: 376)hCV2084294 C/T ATTTTCATCCTGGATCAGAAC ATTTTCATCCTGGATCAGAAT (SEQAGTTGCCCAGGATCATATGT (SEQ (SEQ ID NO: 377) ID NO: 378) ID NO: 379)hCV2084295 C/T GCTAAAGACTTGCTAAGAGTTTG TGCTAAAGACTTGCTAAGAGTTTATGTGTAACTTCAGGAAAATGTCTTA (SEQ ID NO: 380) (SEQ ID NO: 381) (SEQ ID NO:382) hCV2084296 C/T GGAATTCTGCTGTAAGGC (SEQ AAGGAATTCTGCTGTAAGGT (SEQ IDCTCCTGGCTGTTCCAGATAT (SEQ ID NO: 383) NO: 384) ID NO: 385) hCV2084297A/C ACTAGGAACTCTCTCCCCAAT CTAGGAACTCTCTCCCCAAG (SEQ TGTTGTCCCCTCTGACTCTC(SEQ (SEQ ID NO: 386) ID NO: 387) ID NO: 388) hCV2084298 G/TGCACCAAAGAAAGGGATAAAC GCACCAAAGAAAGGGATAAAA (SEQ CCTCATCGAGTTTTGGAGTCT(SEQ (SEQ ID NO: 389) ID NO: 390) ID NO: 391) hCV2084301 C/TCACAGTAAATTCGGTGTTAGTTAT CACAGTAAATTCGGTGTTAGTTATTTCCACTGGTGATTTAAAACAGA C (SEQ ID NO: 392) (SEQ ID NO: 393) (SEQ ID NO:394) hCV261080 A/C CAAGCTATGTGTGTTCCTGATAAA AAGCTATGTGTGTTCCTGATAACCACATGTTTGGGCTCATTTCTATCA (SEQ ID NO: 395) (SEQ ID NO: 396) (SEQ ID NO:397) hCV26465573 A/C GCCCAGCCAAATATCTTAATCAA GCCCAGCCAAATATCTTAATCACCCCCTGTGGATTATCTCTAGCTAAC (SEQ ID NO: 398) (SEQ ID NO: 399) T (SEQ IDNO: 400) hCV27106358 A/C GGTGGGGTCAACATTACTAAA GGTGGGGTCAACATTACTAAC(SEQ GCTGAGGCCACCCAAACTAAATA (SEQ ID NO: 401) ID NO: 402) (SEQ ID NO:403) hCV27106365 G/T GAGAATGAGATAAGCCTCAAGAG AGAGAATGAGATAAGCCTCAAGATCATAGAGAGTCTTTGTGCTCTGGTT (SEQ ID NO: 404) (SEQ ID NO: 405) GTA (SEQ IDNO: 406) hCV27106385 A/G TCACACTGTCAGACACATCT (SEQ CACACTGTCAGACACATCC(SEQ ID AAGGGGCTTCTTGAGAGGAAATGA ID NO: 407) NO: 408) (SEQ ID NO: 409)hCV2720238 A/G CTACATCACCCTCTTTGCAATA ACATCACCCTCTTTGCAATG (SEQ IDCGGTGGTTCTTCACAGGTTTCTAAT (SEQ ID NO: 410) NO: 411) A (SEQ ID NO: 412)hCV2720250 C/T TTTATCACAATGCAAACTTCGC CTTTATCACAATGCAAACTTCGTCTGCAGGGATTGACTGGTTTTGTTA (SEQ ID NO: 413) (SEQ ID NO: 414) (SEQ ID NO:415) hCV2720255 G/T AGCTTTTGCAAGCTCAAAATTAC AGCTTTTGCAAGCTCAAAATTAACAGGCCACCACTGTGAAAGTAA (SEQ ID NO: 416) (SEQ ID NO: 417) (SEQ ID NO:418) hCV27467945 A/G AGTGCTTTTGCGACATGAT (SEQ GTGCTTTTGCGACATGAC (SEQ IDAGGACAGTCCTGGAGACTATCTTTA ID NO: 419) NO: 420) AAGA (SEQ ID NO: 421)hCV27471935 C/G GCTTTGTCAGAACTGCTACTAAC GCTTTGTCAGAACTGCTACTAAGCAGTGTCCAAGAAGGCTTGACTT (SEQ ID NO: 422) (SEQ ID NO: 423) (SEQ ID NO:424) hCV27508808 A/C ACAACAGACGGCTGAGTA (SEQ CAACAGACGGCTGAGTC (SEQ IDAGTGGTTCTCAAGGTGTGGTCTTA ID NO: 425) NO: 426) (SEQ ID NO: 427)hCV27936085 C/T GCTGTTGTCCTCATTATACAAATG GCTGTTGTCCTCATTATACAAATGACTCCCGTTAATTCCCAAAGTGTTAC G (SEQ ID NO: 428) (SEQ ID NO: 429) TT (SEQ IDNO: 430) hCV27952715 A/G TGGGCAATCATATCCACTCT (SEQ GGGCAATCATATCCACTCC(SEQ ID GCCCTTTGCCAAGCGATACT (SEQ ID NO: 431) NO: 432) ID NO: 433)hCV28024675 C/T GCTGACTGAACCACAGG (SEQ ID AGCTGACTGAACCACAGA (SEQ IDGAAGTGGGCGGCAGAGAA (SEQ ID NO: 434) NO: 435) NO: 436) hCV29349404 A/CAGTCTATGTTATCAGGCCACTAAT GTCTATGTTATCAGGCCACTAAGGATGCTGTGGTCTGAACGTTTATGT (SEQ ID NO: 437) (SEQ ID NO: 438) (SEQ ID NO:439) hCV29349406 G/T CTTCCTCATGCCCAAAGG (SEQ TCTTCCTCATGCCCAAAGT (SEQ IDGAGGTGACAGCGATTAGGGAGTAG ID NO: 440) NO: 441) (SEQ ID NO: 442)hCV29619986 C/T GCCCTTCTCAGTGAATCTCG GCCCTTCTCAGTGAATCTCA (SEQ IDCTGGTGGACAGACACAACCTAAAC (SEQ ID NO: 443) NO: 444) (SEQ ID NO: 445)hCV2989999 A/C TGATAAGAGGCAGAGTTTAATTCA TGATAAGAGGCAGAGTTTAATTCACCACACACCCTTGGGCATTAATTAGT A (SEQ ID NO: 446) (SEQ ID NO: 447) (SEQ IDNO: 448) hCV2990018 C/T CAGCCTTGGAGTTCACC (SEQ ID GCAGCCTTGGAGTTCACT(SEQ ID TGTGCTCAGCAGAAAAGATATAT NO: 449) NO: 450) (SEQ ID NO: 451)hCV29927086 C/T CAGGGTGTCGAGAACAAC (SEQ TCAGGGTGTCGAGAACAAT (SEQ IDCTCAGTCAAATGTAAGGCAGATACT ID NO: 452) NO: 453) GT (SEQ ID NO: 454)hCV30243123 C/T CCCATGTGGGAAAGTTCG (SEQ TCCCATGTGGGAAAGTTCA (SEQ IDCTCAGAACAGCCTAAATTTTAGGGC ID NO: 455) NO: 456) TTTAT (SEQ ID NO: 457)hCV30279129 C/T GCGCTAATTACACTACCAAATG GTAGCGCTAATTACACTACCAAATAGAACTCTATAACTGCCTAGCAAGAT (SEQ ID NO: 458) (SEQ ID NO: 459) TATGC (SEQID NO: 460) hCV30377542 G/T CAATGGCAAAGCTGTTAGTG ACAATGGCAAAGCTGTTAGTT(SEQ GCTGGGATTATAGGTGTGCACTACT (SEQ ID NO: 461) ID NO: 462) (SEQ ID NO:463) hCV30449508 A/C ACTGCTTCTAGCCCAGTT (SEQ ID ACTGCTTCTAGCCCAGTG (SEQID ACCTAAGGCAAGCCATCTGATACA NO: 464) NO: 465) (SEQ ID NO: 466)hCV30611467 C/T TCTACCAATCAATAAGGTAAGACA CTTCTACCAATCAATAAGGTAAGACAGCCAGGCACCTTCTCAGTCTAT G (SEQ ID NO: 467) A (SEQ ID NO: 468) (SEQ ID NO:469) hCV31222784 A/C TCCATGTGGCCAGAATGAA (SEQ CCATGTGGCCAGAATGAC (SEQ IDGCATTCAGGGTTCTCATTTCATCTC ID NO: 470) NO: 471) T (SEQ ID NO: 472)hCV31222786 A/T ACACTGTGGTAAATGCTGTATT GACACTGTGGTAAATGCTGTATACCCAGCCATATGGAACTGTAAGT (SEQ ID NO: 473) (SEQ ID NO: 474) (SEQ ID NO:475) hCV31222798 G/T AGGCAGCTTTCTCATATTGC (SEQ CAAGGCAGCTTTCTCATATTGA(SEQ ATCGTGAATGAGGAGTTGCCATCTA ID NO: 476) ID NO: 477) (SEQ ID NO: 478)hCV31222811 A/T TCCCTGTGGATGAACTGTAT (SEQ TCCCTGTGGATGAACTGTAA (SEQ IDGATTGGCCAAGACTCAGTTACTGTT ID NO: 479) NO: 480) (SEQ ID NO: 481)hCV31222825 A/G GGGAAGCAAAATTAACCTTTACT GGGAAGCAAAATTAACCTTTACCCACATTTGCCAGAGATGCACTTCTA (SEQ ID NO: 482) (SEQ ID NO: 483) (SEQ ID NO:484) hCV31222826 C/T TGAAGCTCACCACTAAGAATTTAT TGAAGCTCACCACTAAGAATTTATATCACAACTACCCCAGGAAACAACT AC (SEQ ID NO: 485) (SEQ ID NO: 486) (SEQ ID NO:487) hCV31222838 G/T GATGGGTTAAAATGGGCAATTC TGATGGGTTAAAATGGGCAATTAGCTAACAGTTGCTTCCATCTCTACA (SEQ ID NO: 488) (SEQ ID NO: 489) (SEQ ID NO:490) hCV3169817 A/G TGTATGAAGTGCTGAGGATAAATA TGTATGAAGTGCTGAGGATAAATAGATTTCCCCCACCAACACACATAC A (SEQ ID NO: 491) (SEQ ID NO: 492) (SEQ ID NO:493) hCV31985582 A/G CTAATAAATAATGAATATGCTGCA ATAAATAATGAATATGCTGCACCGGCTTCCAGCTCCATCCAAGTTG CCA (SEQ ID NO: 494) (SEQ ID NO: 495) (SEQ ID NO:496) hCV31985592 C/T TCACCAGGTCACTGCC (SEQ ID TTCACCAGGTCACTGCT (SEQ IDGCAGTTTTCTGCCTCCAGGAAATAC NO: 497) NO: 498) (SEQ ID NO: 499) hCV31985602G/T TTTTTGCGGCAGATGAC (SEQ ID TTTTTGCGGCAGATGAA (SEQ IDGGCTTGTTTTGGGAGAGTATG (SEQ NO: 500) NO: 501) ID NO: 502) hCV3220380 C/TGATGGTCACAGTTATGATTCCC GATGGTCACAGTTATGATTCCT (SEQCCTGGGTGACAGAATGAGACTC (SEQ ID NO: 503) ID NO: 504) (SEQ ID NO: 505)hCV3220386 C/T CTCCCACGGCTTGTAATC (SEQ ID CTCCCACGGCTTGTAATT (SEQ IDGCACATTTAGCCAATTTCAACACAT NO: 506) NO: 507) AT (SEQ ID NO: 508)hCV7537756 C/G TGGAGCTCAAATGTTGGTTAG TGGAGCTCAAATGTTGGTTAC (SEQCCTGTTCTTGCAAGGAGGTGATC (SEQ ID NO: 509) ID NO: 510) (SEQ ID NO: 511)hCV7537839 G/T CATCTGTCTGCTTCTCACAG (SEQ CATCTGTCTGCTTCTCACAT (SEQ IDGTCTGGAAGGCAAAAAGATC (SEQ ID NO: 512) NO: 513) ID NO: 514) hCV7537857A/C GGCCAGTCCTCACACAT (SEQ ID GGCCAGTCCTCACACAG (SEQ IDAAGACTCCCAAGGATAGCGTGTTA NO: 515) NO: 516) G (SEQ ID NO: 517) hCV7538743C/G TGGACATTTTGTTGTGTTTGC TTGGACATTTTGTTGTGTTTGG (SEQCCACCCATATCACATGTCATCAGT (SEQ ID NO: 518) ID NO: 519) (SEQ ID NO: 520)hCV7538755 C/G TTAGTCATTTAAAGTCAGGTTAAT TAGTCATTTAAAGTCAGGTTAATGTTCGGTGTGGCCTTGTGAG (SEQ ID GTTC (SEQ ID NO: 521) G (SEQ ID NO: 522) NO:523) hCV7538761 C/T GTGTACCAAATTCATTGCTCTAAT GTGTACCAAATTCATTGCTCTAATTCAAAGCTTCTTGATGCCTTGTTT C (SEQ ID NO: 524) (SEQ ID NO: 525) (SEQ ID NO:526) hCV8367042 C/G GGCACACACCACCATTTC (SEQ GGCACACACCACCATTTG (SEQ IDGGCAAAGACAGGCAGATCACT ID NO: 527) NO: 528) (SEQ ID NO: 529) hCV8367043A/G GGAGAAACTCAGTGCCAATTT GGAGAAACTCAGTGCCAATTC (SEQCATTGAGTATTTCTAAGCTGCTCGA (SEQ ID NO: 530) ID NO: 531) TAGA (SEQ ID NO:532) hDV70267720 C/T GGAATGTCATCCAGCCATAAAG GGAATGTCATCCAGCCATAAAAGCCTTTCGTGTGGGTTCTTTAACT (SEQ ID NO: 533) (SEQ ID NO: 534) (SEQ ID NO:535) hDV71045748 A/G AACTGACGACCAAGACCA (SEQ ACTGACGACCAAGACCG (SEQ IDTGAGTGGTGCCTGCCTTACTATT ID NO: 536) NO: 537) (SEQ ID NO: 538)hDV79877074 C/T CTGTCTCCGAGAGAGGG (SEQ ID TCTCCGAGAGAGGCTCTAA (SEQ IDGGGCTGATGCTTGGAGATTGT NO: 539) NO: 540) (SEQ ID NO: 541)

TABLE 4 Interrogated Interrogated Threshold SNP rs LD SNP LD SNP rsPower r² r² hCV11283764 rs10889677 hCV1272302 rs2201841 0.51 0.9 0.9325hCV11283764 rs10889677 hCV261079 rs10889676 0.51 0.9 1 hCV11283764rs10889677 hCV2720251 rs11465817 0.51 0.9 0.9095 hCV11314640 rs1833754hCV27106364 rs4262088 0.51 0.9 1 hCV11314640 rs1833754 hCV7538744rs1422880 0.51 0.9 1 hCV11314640 rs1833754 hCV7538751 rs1422879 0.51 0.91 hCV11314640 rs1833754 hCV7538752 rs1363669 0.51 0.9 1 hCV11314640rs1833754 hDV70836316 rs17056705 0.51 0.9 1 hCV1272302 rs2201841hCV11283764 rs10889677 0.51 0.9 0.9325 hCV1272302 rs2201841 hCV261079rs10889676 0.51 0.9 0.9325 hCV15894459 rs2546892 hCV15824051 rs28536970.51 0.9 0.9345 hCV15894459 rs2546892 hCV27467946 rs3181226 0.51 0.90.9345 hCV1994965 rs953861 hCV1994960 rs4921483 0.51 0.9 1 hCV1994965rs953861 hCV1994973 rs1157509 0.51 0.9 1 hCV1994965 rs953861 hCV1994974rs1157510 0.51 0.9 1 hCV1994965 rs953861 hCV1994986 rs11749573 0.51 0.91 hCV1994965 rs953861 hCV30017148 rs9313808 0.51 0.9 1 hCV1994965rs953861 hCV7538743 rs1363670 0.51 0.9 1 hCV1994990 rs6861600hCV11264637 rs6864071 0.51 0.9 0.9596 hCV1994990 rs6861600 hCV11269323rs11135059 0.51 0.9 0.9596 hCV1994990 rs6861600 hCV1994971 rs77253390.51 0.9 0.9547 hCV1994990 rs6861600 hCV27106359 rs12522665 0.51 0.9 1hCV1994990 rs6861600 hCV27106365 rs4379175 0.51 0.9 0.9564 hCV1994990rs6861600 hCV29349404 rs7704367 0.51 0.9 1 hCV1994990 rs6861600hCV31985582 rs6556412 0.51 0.9 0.9568 hCV2084270 rs2082412 hCV15803290rs2421047 0.51 0.9 1 hCV2084270 rs2082412 hCV15879826 rs2288831 0.51 0.91 hCV2084270 rs2082412 hCV2084281 rs7730390 0.51 0.9 1 hCV2084270rs2082412 hCV2084293 rs3212227 0.51 0.9 0.9699 hCV2084270 rs2082412hCV27471935 rs3212217 0.51 0.9 0.9699 hCV2084270 rs2082412 hCV27486507rs3212219 0.51 0.9 0.9699 hCV2084270 rs2082412 hCV27508808 rs32122180.51 0.9 1 hCV2084270 rs2082412 hCV27883435 rs4921442 0.51 0.9 0.9451hCV2084270 rs2082412 hCV29349409 rs6859018 0.51 0.9 0.9699 hCV2084270rs2082412 hCV29619986 rs10072923 0.51 0.9 1 hCV2084270 rs2082412hCV29927086 rs3213094 0.51 0.9 0.9699 hCV2084270 rs2082412 hCV30449508rs3212220 0.51 0.9 1 hCV2084270 rs2082412 hCV30557642 rs10056599 0.510.9 1 hCV2084270 rs2082412 hDV71045748 rs6894567 0.51 0.9 0.9476hCV2084270 rs2082412 hDV75439995 rs3213097 0.51 0.9 1 hCV2084281rs7730390 hCV15803290 rs2421047 0.51 0.9 0.9061 hCV2084281 rs7730390hCV2084270 rs2082412 0.51 0.9 1 hCV2084281 rs7730390 hCV2084293rs3212227 0.51 0.9 1 hCV2084281 rs7730390 hCV27471935 rs3212217 0.51 0.91 hCV2084281 rs7730390 hCV27486507 rs3212219 0.51 0.9 1 hCV2084281rs7730390 hCV27508808 rs3212218 0.51 0.9 1 hCV2084281 rs7730390hCV29349409 rs6859018 0.51 0.9 1 hCV2084281 rs7730390 hCV29619986rs10072923 0.51 0.9 0.9061 hCV2084281 rs7730390 hCV29927086 rs32130940.51 0.9 1 hCV2084281 rs7730390 hCV30449508 rs3212220 0.51 0.9 0.9061hCV2084281 rs7730390 hCV30557642 rs10056599 0.51 0.9 1 hCV2084281rs7730390 hDV75439995 rs3213097 0.51 0.9 0.905 hCV2084293 rs3212227hCV15803290 rs2421047 0.51 0.9 1 hCV2084293 rs3212227 hCV15879826rs2288831 0.51 0.9 1 hCV2084293 rs3212227 hCV2084270 rs2082412 0.51 0.90.9699 hCV2084293 rs3212227 hCV2084281 rs7730390 0.51 0.9 1 hCV2084293rs3212227 hCV27471935 rs3212217 0.51 0.9 1 hCV2084293 rs3212227hCV27486507 rs3212219 0.51 0.9 1 hCV2084293 rs3212227 hCV27508808rs3212218 0.51 0.9 1 hCV2084293 rs3212227 hCV27883435 rs4921442 0.51 0.90.9451 hCV2084293 rs3212227 hCV29349409 rs6859018 0.51 0.9 1 hCV2084293rs3212227 hCV29619986 rs10072923 0.51 0.9 1 hCV2084293 rs3212227hCV29927086 rs3213094 0.51 0.9 1 hCV2084293 rs3212227 hCV30449508rs3212220 0.51 0.9 1 hCV2084293 rs3212227 hCV30557642 rs10056599 0.510.9 0.9699 hCV2084293 rs3212227 hDV71045748 rs6894567 0.51 0.9 0.9476hCV2084293 rs3212227 hDV75439995 rs3213097 0.51 0.9 1 hCV2084294rs3213120 hCV31985602 rs3213119 0.51 0.9 1 hCV2084296 rs2853696hCV11316602 rs1865014 0.51 0.9 1 hCV2084296 rs2853696 hCV2084251rs10515780 0.51 0.9 1 hCV2084296 rs2853696 hCV2084252 rs10866711 0.510.9 1 hCV2084296 rs2853696 hCV2084259 rs7708700 0.51 0.9 1 hCV2084296rs2853696 hCV2084263 rs10515782 0.51 0.9 1 hCV2084296 rs2853696hCV2084265 rs7736656 0.51 0.9 1 hCV2084296 rs2853696 hCV2084266rs10042630 0.51 0.9 0.9704 hCV2084296 rs2853696 hCV2084274 rs14330470.51 0.9 1 hCV2084296 rs2853696 hCV2084277 rs6874870 0.51 0.9 1hCV2084296 rs2853696 hCV27936085 rs4921437 0.51 0.9 0.9421 hCV2084296rs2853696 hCV30629526 rs4921458 0.51 0.9 1 hCV2084296 rs2853696hCV7537839 rs1368439 0.51 0.9 1 hCV26465573 rs11209030 hCV29129920rs6677188 0.51 0.9 0.9607 hCV26465573 rs11209030 hCV31222784 rs112090310.51 0.9 0.9628 hCV26465573 rs11209030 hCV31222785 rs12045232 0.51 0.90.9607 hCV2720238 rs11209032 hCV2720231 rs11209034 0.51 0.9 0.9774hCV2720238 rs11209032 hCV2720233 rs11209033 0.51 0.9 0.9769 hCV2720238rs11209032 hCV3277187 rs7546245 0.51 0.9 0.9304 hCV2720238 rs11209032hCV3277191 rs12119179 0.51 0.9 0.9541 hCV27467945 rs3181225 hCV15824051rs2853697 0.51 0.9 1 hCV27467945 rs3181225 hCV16044033 rs2569254 0.510.9 1 hCV27467945 rs3181225 hCV2084260 rs13153734 0.51 0.9 0.9034hCV27467945 rs3181225 hCV2084282 rs2099327 0.51 0.9 0.9338 hCV27467945rs3181225 hCV27467946 rs3181226 0.51 0.9 1 hCV27467945 rs3181225hCV31985611 rs13161132 0.51 0.9 0.9259 hCV27952715 rs4655692 hCV2990015rs7528924 0.51 0.9 1 hCV2989999 rs1343152 hCV2990001 rs12030948 0.51 0.91 hCV2990018 rs7530511 hCV16078411 rs2863212 0.51 0.9 0.9186 hCV2990018rs7530511 hCV27868367 rs4655530 0.51 0.9 0.9192 hCV2990018 rs7530511hCV27868368 rs4655693 0.51 0.9 1 hCV2990018 rs7530511 hCV31222825rs10889671 0.51 0.9 0.9192 hCV30279129 rs10489629 hCV2990017 rs75186600.51 0.9 0.9444 hCV30611467 rs6869411 hCV31985588 rs6878967 0.51 0.9 1hCV30611467 rs6869411 hCV31985590 rs11738529 0.51 0.9 1 hCV30611467rs6869411 hDV70836317 rs17056706 0.51 0.9 1 hCV31222784 rs11209031hCV26465573 rs11209030 0.51 0.9 0.9628 hCV31222784 rs11209031hCV29129920 rs6677188 0.51 0.9 1 hCV31222784 rs11209031 hCV30423493rs7539328 0.51 0.9 0.9266 hCV31222784 rs11209031 hCV31222785 rs120452320.51 0.9 1 hCV31222786 rs1857292 hCV11283811 rs4655536 0.51 0.9 1hCV31222786 rs1857292 hCV2720226 rs2863209 0.51 0.9 1 hCV31222825rs10889671 hCV27868367 rs4655530 0.51 0.9 1 hCV31222825 rs10889671hCV27868368 rs4655693 0.51 0.9 0.9192 hCV31222825 rs10889671 hCV2990018rs7530511 0.51 0.9 0.9192 hCV31222826 rs10789229 hCV31222830 rs127518140.51 0.9 0.9808 hCV31985602 rs3213119 hCV2084294 rs3213120 0.51 0.9 1hCV7537756 rs1368437 hCV1030157 rs254837 0.51 0.9 0.9396 hCV7537756rs1368437 hCV25633374 rs12520035 0.51 0.9 1 hCV7537756 rs1368437hCV28001193 rs4921466 0.51 0.9 0.9425 hCV7537839 rs1368439 hCV11316602rs1865014 0.51 0.9 1 hCV7537839 rs1368439 hCV2084251 rs10515780 0.51 0.91 hCV7537839 rs1368439 hCV2084252 rs10866711 0.51 0.9 1 hCV7537839rs1368439 hCV2084259 rs7708700 0.51 0.9 1 hCV7537839 rs1368439hCV2084263 rs10515782 0.51 0.9 1 hCV7537839 rs1368439 hCV2084265rs7736656 0.51 0.9 1 hCV7537839 rs1368439 hCV2084266 rs10042630 0.51 0.90.9705 hCV7537839 rs1368439 hCV2084274 rs1433047 0.51 0.9 1 hCV7537839rs1368439 hCV2084277 rs6874870 0.51 0.9 1 hCV7537839 rs1368439hCV2084296 rs2853696 0.51 0.9 1 hCV7537839 rs1368439 hCV27936085rs4921437 0.51 0.9 0.9422 hCV7537839 rs1368439 hCV30629526 rs49214580.51 0.9 1 hCV8367042 rs1008193 hCV11728628 rs2000252 0.51 0.9 0.9771hCV8367042 rs1008193 hCV29503362 rs6682033 0.51 0.9 1 hCV8367043rs1343151 hDV81067815 rs41396545 0.51 0.9 0.9168 hDV71045748 rs6894567hCV15803290 rs2421047 0.51 0.9 0.9527 hDV71045748 rs6894567 hCV15879826rs2288831 0.51 0.9 0.9496 hDV71045748 rs6894567 hCV2084270 rs20824120.51 0.9 0.9476 hDV71045748 rs6894567 hCV2084293 rs3212227 0.51 0.90.9476 hDV71045748 rs6894567 hCV27471935 rs3212217 0.51 0.9 0.9476hDV71045748 rs6894567 hCV27486507 rs3212219 0.51 0.9 0.9476 hDV71045748rs6894567 hCV27508808 rs3212218 0.51 0.9 0.9483 hDV71045748 rs6894567hCV27883435 rs4921442 0.51 0.9 0.9026 hDV71045748 rs6894567 hCV29349409rs6859018 0.51 0.9 0.9476 hDV71045748 rs6894567 hCV29619986 rs100729230.51 0.9 0.9527 hDV71045748 rs6894567 hCV29927086 rs3213094 0.51 0.90.9476 hDV71045748 rs6894567 hCV30449508 rs3212220 0.51 0.9 0.9527hDV71045748 rs6894567 hCV30557642 rs10056599 0.51 0.9 0.9476 hDV71045748rs6894567 hDV75439995 rs3213097 0.51 0.9 0.9523

TABLE 5 rs7530511-rs11465804-rs10889671-rs11209026-rs1857292 haplotypesSample Set 1 Sample Set 2 Sample Set 3 No. (Frequency) in No.(Frequency) in No. (Frequency) in Haplotype^(a,b) Case Control CaseControl Case Control CTGGA 754 (0.818)  704 (0.769)  791 (0.802)  747(0.755)  795 (0.828)  645 (0.760)  TTAGT 69 (0.075) 103 (0.112)  68(0.069) 82 (0.083) 74 (0.077) 78 (0.092) CGGAA 36 (0.039) 47 (0.051) 45(0.046) 79 (0.080) 33 (0.034) 52 (0.061) CTGGT 31 (0.034) 21 (0.023) 31(0.031) 36 (0.036) 22 (0.023) 28 (0.033) TTAGA 23 (0.025) 26 (0.028) 20(0.020) 27 (0.027) 28 (0.029) 31 (0.037) Other  9 (0.010) 15 (0.016) 31(0.031) 19 (0.019)  8 (0.008) 14 (0.017) Sample Set 1 Sample Set 2Sample Set 3 No. (Frequency) in No. (Frequency) in No. (Frequency) inCombined Haplotype Case Control OR Case Control OR Case Control ORP_(comb) ^(d) Protective^(c) 105 (0.114) 150 (0.164) 113 (0.115) 161(0.163) 107 (0.112) 130 (0.153) All Other 817 (0.886) 766 (0.836) 0.66873 (0.885) 829 (0.837) 0.67 853 (0.889) 718 (0.847) 0.69 4.32E−07^(a)Haplotype estimates were from the pseudo-Gibbs algorithm in theSNPAnalyzer program. ^(b)These haplotypes consist of SNPs: rs7530511,rs11465804, rs10889671, rs11209026 and rs1857292, respectively.^(c)TTAGT and CGGAA haplotypes combined. ^(d)Continuity-correctedMantel-Haenszel P-value.

TABLE 6 rs7530511-rs10889671-rs11209026 haplotypes Sample Set 1 SampleSet 2 Sample Set 3 No. (Frequency) in No. (Frequency) in No. (Frequency)in Combined Haplotype^(a,b) Case Control Case Control Case ControlP_(comb) ^(c) CGG 783 (0.852)  727 (0.795) 830 (0.844)  787 (0.798) 818(0.855) 677 (0.801) 3.88E−08 TAG 91 (0.099) 128 (0.140) 88 (0.090) 108(0.110) 100 (0.105) 107 (0.127) CGA 39 (0.042)  54 (0.059) 51 (0.052) 86 (0.087)  33 (0.035)  55 (0.065) Other  6 (0.007)   5 (0.006) 14(0.014)   5 (0.005)   6 (0.006)   6 (0.007) ^(a)Haplotype estimates werefrom the pseudo-Gibbs algorithm in the SNPAnalyzer program. ^(b)Thesehaplotypes consist of SNPs: rs7530511, rs10889671, and rs11209026,respectively. ^(c)Continuity-corrected Mantel-Haenszel P-value for TAG+ CGA

TABLE 7 Twenty-three marker haplotypes Combined Sample Set 1 Sample Set2 Sample Set 3 Analysis Haplotype^(a,b) Case Control OR P^(c) CaseControl OR P^(c) Case Control OR P^(c) OR^(d) P^(e) CTGGTGCTGGGTGC 248217 1.18 0.133 266 252 1.07 0.506 280 220 1.18 0.127 1.139 0.034CCTACCAAA CCGATAACGGTTAG 181 184 0.97 0.815 206 200 1.04 0.781 215 1571.27 0.047 1.081 0.252 CCTCCAACG TTAATGACAGTTGC 65 100 0.62 0.0042 61 750.80 0.215 73 77 0.82 0.268 0.736 0.0022 TCTCCCTAG CCGATAATGGTTGC 85 761.12 0.510 60 72 0.82 0.281 65 69 0.82 0.281 0.921 0.440 TTACTCAAGCTAATGATGGGAGC 79 62 1.28 0.162 76 70 1.09 0.667 75 52 1.30 0.168 1.2160.064 CCTCCCAAG CCGAGGCTGATTAC 36 47 0.75 0.217 47 75 0.61 0.0089 31 510.52 0.0063 0.618 0.000113 CCTCCCAAG CTGGTGCTGGGTGC 35 38 0.91 0.176 3736 1.03 1.000 36 34 0.93 0.808 0.955 0.792 CCTACCAAG CCGATAATGGTTGC 2332 0.70 0.220 25 26 0.96 0.888 37 26 1.27 0.372 0.961 0.860 TATCTAACGCCGATAACGGTTAG 21 23 0.90 0.762 34 30 1.14 0.703 20 17 1.04 1.000 1.0350.906 CCTCCCAAG Other 151 135 1.13 0.368 174 148 1.21 0.128 128 145 0.750.030 1.017 0.849 ^(a)Haplotypes built on: rs7530511, rs10489629,rs4655692, rs2201841, rs11465804, rs10489628, rs1343152, rs10789229,rs10889671, rs11209026, rs10889674, rs12085634, rs1343151, rs1008193,rs6693831, rs10889675, rs11465827, rs10889677, rs4655531, rs11209030,rs1857292, rs11209031, and rs11209032, respectively. ^(b)Pseudo-Gibbssampling algorithm in SNPAnalyzer used ^(c)Fisher's Exact test^(d)Mantel-Haenszel common odds ratio ^(e)Continuity-correctedMantel-Haenszel P-value

TABLE 8 Twelve marker reduced haplotypes Sample Set 1 Sample Set 2Sample Set 3 Haplotype^(a,b) Cases Controls OR P-value^(c) CasesControls OR P-value^(c) Cases Controls OR P-value^(c) GGGTCCTACCAA 256217 1.374 0.055 270 255 1.125 0.476 280 225 1.238 0.227 AATTGCTCCACG 190186 1.092 0.954 213 202 1.105 0.581 220 161 1.372 0.043 AGTTCCTCCCAG 116156 0.729 0.0070 124 174 0.668 0.0017 114 143 0.676 0.0029 AATTCATCTCAG90 75 1.291 0.255 71 77 0.932 0.609 76 72 0.963 0.668 AGGACCTCCCAG 85 661.394 0.127 78 74 1.082 0.800 77 48 1.530 0.077 GGGTCCTACCAG 36 39 0.9610.724 38 38 1.019 1.000 38 35 0.994 0.905 AATTGCTCCCAG 34 42 0.836 0.35056 57 1.000 0.923 32 38 0.760 0.223 AATTCATCTACG 24 34 0.727 0.183 28 261.100 0.890 37 27 1.270 0.524 Other 93 99 0.977 0.595 108 81 1.421 0.04786 99 0.766 0.062 Frequency Haplotype Case Control OR^(d) P^(e)AGTTCCTCCCAG 0.123 0.172 0.677 3.19E−07 All Other 0.877 0.828^(a)Haplotypes built on: rs2201841, rs10489628, 10889674, rs12085634,rs1008193, rs10889675, rs11465827, rs10889677, rs4655531, rs11209030,rs11209031, and rs11209032, respectively. ^(b)Haplotype estimates werefrom the pseudo-Gibbs algorithm in the SNPAnalyzer program. ^(c)Fisher'sExact test ^(d)Mantel-Haenszel Common OR ^(e)Continuity-CorrectedMantel-Haenszel P-value

TABLE 9 lndiv 9-SNP control_freq case_freq SNP set haplotype (counts)(counts) Hap.P rs2546892 S0048 GAGCCATTG 0.170 (156) 0.119 (111)0.001739 rs1433048 S0056A GAGCCATTG 0.189 (188) 0.097 (96)  8.51E−09rs6894567 A0019 GAGCCATTG 0.164 (138) 0.121 (116) 0.011771 rs17860508rs7709212 Comb P 2.2E−11 rs953861 rs6869411 rs1833754 rs6861600

TABLE 10 control_freq case_freq SNP set (counts) (counts) Hap.P GlobalS0048 rs1368437 GGTGTTTTC 0.022 (20) 0.028 (26) 0.460695 0.003899rs2082412 CGTATTCGC 0.176 (161) 0.187 (174) 0.510331 0.003899 rs7730390CGTGGTCGT 0.190 (174) 0.205 (191) 0.450394 0.003899 rs3181225 GGTGTTCGC0.069 (63) 0.090 (84) 0.097427 0.003899 rs1368439 CACGTGCGC 0.207 (190)0.144 (134) 0.000429 0.003899 rs3212227 CGTGTTCGC 0.324 (297) 0.343(320) 0.383258 0.003899 rs3213120 Other 0.013 (11) 0.004 (3) rs3213119S0056A rs2853696 CGTATTCGC 0.176 (175) 0.173 (172) 8.12E−01 5.28E−05GGTGTTCGC 0.067 (66) 0.101 (100) 4.01E−03 5.28E−05 CGTGGTCGT 0.181 (180)0.226 (225) 1.42E−02 5.28E−05 CACGTGCGC 0.223 (221) 0.140 (139) 3.48E−065.28E−05 CGTGTTCGC 0.308 (306) 0.325 (324) 4.58E−01 5.28E−05 GGTGTTTTC0.032 (31) 0.026 (25) 3.99E−01 5.28E−05 Other 0.013 (13) 0.009 (8) A0019GGTGTTTTC 0.030 (25) 0.021 (20) 0.222102 0.023735 CGTATTCGC 0.171 (145)0.165 (158) 0.714954 0.023735 GGTGTTCGC 0.074 (62) 0.083 (79) 0.488170.023735 CGTGGTCGT 0.175 (147) 0.217 (208) 0.02158 0.023735 CACGTGCGC0.212 (179) 0.162 (155) 0.007201 0.023735 CGTGTTCGC 0.331 (280) 0.337(324) 0.793763 0.023735 Other 0.007 (6) 0.015 (14) CACGTGCGC Comb P1.03E−09 Global Comb P 2.84E−07

TABLE 11 frequency frequency of minor of minor Genotyped Odds MajorMinor allele in allele in Marker Gene or Imputed P-value Ratio OR95lOR95u allele allele cases controls rs6859018 Imputation 1.31E−10 0.6360.555 0.731 G A 0.150 0.216 rs10072923 Imputation 1.41E−10 0.637 0.5550.731 T C 0.150 0.217 rs2421047 IL12B Imputation 2.05E−10 0.640 0.5580.734 G A 0.150 0.216 rs4921442 UBLCP1 Imputation 2.52E−10 0.641 0.5580.735 C G 0.151 0.217 rs10056599 Imputation 2.55E−10 0.642 0.559 0.736 TG 0.152 0.217 rs3213097 IL12B Imputation 2.60E−10 0.641 0.559 0.736 A T0.150 0.216 rs3212218 IL12B Imputation 2.78E−10 0.642 0.559 0.737 C A0.151 0.216 rs3212219 IL12B Imputation 3.02E−10 0.642 0.560 0.737 C A0.151 0.216 rs3212227 IL12B Genotyping 3.44E−10 0.643 0.560 0.738 T G0.150 0.215 rs7730390 Genotyping 4.08E−10 0.644 0.561 0.739 T C 0.1510.216 rs3213093 IL12B Genotyping 4.30E−10 0.645 0.562 0.740 C T 0.1510.215 rs3213094 IL12B Imputation 5.77E−10 0.649 0.566 0.744 C T 0.1550.219 rs3212220 IL12B Genotyping 9.02E−10 0.650 0.566 0.746 G T 0.1520.215 rs2082412 Genotyping 1.26E−09 0.652 0.568 0.748 G A 0.152 0.214rs3212217 IL12B Genotyping 1.26E−09 0.652 0.568 0.749 C G 0.152 0.215rs6861600 Genotyping 3.26E−09 0.701 0.623 0.788 C G 0.248 0.320rs12522665 Imputation 4.14E−09 0.703 0.624 0.790 C T 0.249 0.320rs6887695 Genotyping 5.26E−09 0.704 0.626 0.792 G C 0.249 0.320rs6556412 Imputation 6.25E−09 0.702 0.623 0.791 G A 0.253 0.325rs6864071 Imputation 6.25E−09 0.702 0.623 0.791 G A 0.253 0.325rs4379175 Imputation 6.25E−09 0.702 0.623 0.791 G T 0.253 0.325rs6894567 IL12B Genotyping 7.52E−09 0.665 0.579 0.764 A G 0.150 0.210rs7704367 Genotyping 8.26E−09 0.707 0.629 0.796 A C 0.250 0.320rs7725339 Imputation 9.21E−09 0.704 0.625 0.794 G T 0.253 0.324rs11135059 Imputation 1.17E−08 0.706 0.626 0.796 G A 0.254 0.324rs7709212 Genotyping 5.42E−08 0.727 0.648 0.815 T C 0.272 0.339rs6556411 Imputation 2.59E−06 1.318 1.175 1.479 T G 0.366 0.306rs4244437 Imputation 3.41E−06 1.314 1.171 1.474 A G 0.366 0.307 rs983825Imputation 3.41E−06 1.314 1.171 1.474 A C 0.366 0.307 rs6556416Imputation 9.68E−06 1.306 1.160 1.471 C A 0.354 0.297 rs6556405 RNF145Imputation 4.20E−05 0.778 0.690 0.877 T C 0.233 0.280 rs918520Genotyping 7.28E−05 1.289 1.137 1.462 C G 0.252 0.207 rs7715173Imputation 8.49E−05 0.770 0.675 0.877 T C 0.183 0.225 rs6870828Imputation 9.25E−05 1.234 1.110 1.371 T C 0.514 0.462 rs7719425Genotyping 0.000106687 0.773 0.678 0.880 T C 0.184 0.225 rs1422877Imputation 0.000112734 0.798 0.711 0.895 A G 0.326 0.378 rs1549922Imputation 0.000132703 0.814 0.732 0.904 G A 0.448 0.500 rs1473247RNF145 Imputation 0.000145486 0.793 0.704 0.894 T C 0.237 0.282rs4921483 Imputation 0.000145879 1.314 1.141 1.513 G A 0.200 0.161rs1897565 RNF145 Genotyping 0.000150046 0.794 0.704 0.894 T C 0.2350.279 rs6888950 RNF145 Genotyping 0.000151216 0.793 0.703 0.894 T G0.235 0.279 rs12651787 Imputation 0.000169251 0.803 0.717 0.900 T C0.326 0.376 rs4921493 Imputation 0.000251817 0.809 0.722 0.906 T C 0.3240.373 rs10076782 RNF145 Genotyping 0.000288586 0.801 0.711 0.903 G A0.238 0.280 rs1363670 Imputation 0.000361505 1.285 1.120 1.475 G C 0.2040.168 rs1984811 Imputation 0.000371323 1.250 1.105 1.413 A G 0.276 0.234rs1422878 Genotyping 0.000371662 0.818 0.733 0.914 C T 0.317 0.362rs953861 Genotyping 0.000388002 1.283 1.118 1.473 A G 0.205 0.169rs1157509 Imputation 0.000459256 1.280 1.115 1.469 G A 0.203 0.168rs1157510 Imputation 0.000459256 1.280 1.115 1.469 C T 0.203 0.168rs11749573 Imputation 0.000459256 1.280 1.115 1.469 A G 0.203 0.168rs9313808 Imputation 0.000459256 1.280 1.115 1.469 G A 0.203 0.168rs2853694 IL12B Genotyping 0.000544359 0.830 0.747 0.923 G T 0.449 0.495rs4921499 Imputation 0.000588348 1.232 1.094 1.388 G A 0.286 0.246rs4921500 Imputation 0.000588348 1.232 1.094 1.388 G A 0.286 0.246rs7702534 Imputation 0.000588348 1.232 1.094 1.388 G T 0.286 0.246rs254843 Imputation 0.000687505 1.258 1.102 1.437 C T 0.227 0.190rs4921504 Imputation 0.000705248 0.784 0.681 0.902 C G 0.181 0.217rs2421186 Imputation 0.000705248 0.784 0.681 0.902 A C 0.181 0.217rs254852 Imputation 0.000817419 1.254 1.098 1.432 A T 0.223 0.188rs254850 Imputation 0.000817419 1.254 1.098 1.432 C T 0.223 0.188rs254839 Imputation 0.000836466 1.256 1.099 1.436 T A 0.225 0.189rs4921200 Imputation 0.000836466 1.256 1.099 1.436 A T 0.225 0.189rs4921496 Genotyping 0.000990418 1.220 1.084 1.373 C T 0.287 0.249rs10042630 UBLCP1 Imputation 0.001080853 1.249 1.093 1.427 T A 0.2180.184 rs4921458 Imputation 0.001132692 1.248 1.092 1.426 C T 0.218 0.184rs4921437 UBLCP1 Imputation 0.001252363 1.245 1.090 1.423 C T 0.2180.184 rs10515780 UBLCP1 Imputation 0.001252363 1.245 1.090 1.423 G C0.218 0.184 rs10866711 UBLCP1 Imputation 0.001252363 1.245 1.090 1.423 CT 0.218 0.184 rs7708700 UBLCP1 Imputation 0.001252363 1.245 1.090 1.423C T 0.218 0.184 rs10515782 UBLCP1 Imputation 0.001252363 1.245 1.0901.423 T C 0.218 0.184 rs7736656 UBLCP1 Imputation 0.001252363 1.2451.090 1.423 G A 0.218 0.184 rs4921230 Genotyping 0.001269997 0.813 0.7170.922 C T 0.209 0.245 rs12657996 Imputation 0.001330019 0.790 0.6840.912 G A 0.172 0.207 rs1368439 IL12B Genotyping 0.001332138 1.243 1.0891.420 T G 0.217 0.183 rs1865014 Imputation 0.001433642 1.241 1.087 1.418C T 0.216 0.182 rs6874870 Imputation 0.001792749 1.236 1.082 1.412 C T0.216 0.183 rs2853696 IL12B Genotyping 0.001902523 1.234 1.081 1.410 C T0.217 0.184 rs1433047 Imputation 0.002006695 1.233 1.080 1.409 C T 0.2160.183 rs1433048 IL12B Genotyping 0.00236978 1.230 1.076 1.406 A G 0.2180.185 rs270659 Imputation 0.00276249 1.238 1.076 1.423 T C 0.192 0.162rs13178603 RNF145 Imputation 0.004508011 1.212 1.061 1.384 G C 0.2170.187 rs270661 Genotyping 0.004825491 1.207 1.059 1.376 C T 0.215 0.185rs13158488 RNF145 Imputation 0.004904697 1.209 1.059 1.380 T C 0.2160.186 rs17663721 RNF145 Imputation 0.005027418 1.208 1.059 1.379 T C0.216 0.186 rs11574790 IL12B Imputation 0.005211623 1.318 1.086 1.600 GA 0.092 0.071 rs2195940 IL12B Imputation 0.006176876 1.311 1.080 1.591 CT 0.092 0.072 rs2116821 Imputation 0.011425124 0.871 0.782 0.969 C T0.367 0.399 rs7732511 Imputation 0.012287922 1.216 1.043 1.417 G A 0.1600.136 rs1433046 UBLCP1 Imputation 0.015431773 0.876 0.786 0.975 T C0.370 0.402 rs194228 Imputation 0.015866292 0.876 0.787 0.975 G A 0.3690.401 rs2420825 UBLCP1 Imputation 0.015866292 0.876 0.787 0.975 T C0.369 0.401 rs3734104 UBLCP1 Imputation 0.015866292 0.876 0.787 0.975 GC 0.369 0.401 rs17665189 UBLCP1 Imputation 0.015866292 0.876 0.787 0.975T G 0.369 0.401 rs17860508 Genotyping 0.01770095 0.882 0.794 0.978 T C0.465 0.497 rs254837 Imputation 0.018638426 1.234 1.036 1.470 C G 0.1130.094 rs11746138 Imputation 0.025056654 1.190 1.022 1.385 C T 0.1570.136 rs11747112 Imputation 0.025056654 1.190 1.022 1.385 C G 0.1570.136 rs12652431 Imputation 0.027069579 1.213 1.022 1.440 A G 0.1220.104 rs1368437 UBLCP1 Genotyping 0.02847955 1.211 1.020 1.437 C G 0.1180.100 rs12520035 UBLCP1 Imputation 0.033981552 1.202 1.014 1.425 A G0.118 0.101 rs270654 Genotyping 0.036760864 1.198 1.011 1.420 T C 0.1190.102 rs919766 IL12B Genotyping 0.040074923 1.193 1.008 1.412 A C 0.1220.105 rs4921466 Imputation 0.041237398 1.195 1.007 1.418 T C 0.117 0.100rs3181224 Imputation 0.048412617 1.184 1.001 1.401 A G 0.122 0.106

1. A method of determining whether a human has an altered risk forautoinflammatory disease, comprising testing nucleic acid from saidhuman for the presence or absence of a polymorphism selected from thegroup consisting of the polymorphisms as represented by position 101 ofany one of the nucleotide sequences of SEQ ID NOS:219, 21-218, and220-307 or its complement, wherein said polymorphism indicates saidhuman has an altered risk for autoinflammatory disease.
 2. The method ofclaim 1, wherein said autoinflammatory disease is psoriasis or Crohn'sdisease.
 3. The method of claim 1, wherein said altered risk is anincreased risk.
 4. The method of claim 1, wherein said altered risk is adecreased risk. 5-7. (canceled)
 8. The method of claim 1, wherein saidnucleic acid is a nucleic acid extract from a biological sample fromsaid human.
 9. The method of claim 8, wherein said biological sample isblood, saliva, or buccal cells.
 10. The method of claim 8, furthercomprising preparing said nucleic acid extract from said biologicalsample prior to said testing step.
 11. The method of claim 10, furthercomprising obtaining said biological sample from said human prior tosaid preparing step.
 12. The method of claim 1, wherein said testingstep comprises nucleic acid amplification.
 13. The method of claim 12,wherein said nucleic acid amplification is carried out by polymerasechain reaction.
 14. The method of claim 1, further comprisingcorrelating the presence or absence of said polymorphism with an alteredrisk for autoinflammatory disease.
 15. The method of claim 14, whereinsaid correlating step is performed by computer software.
 16. The methodof claim 1, wherein said testing is performed using sequencing, 5′nuclease digestion, molecular beacon assay, oligonucleotide ligationassay, size analysis, single-stranded conformation polymorphismanalysis, or denaturing gradient gel electrophoresis (DGGE).
 17. Themethod of claim 1, wherein said testing is performed using anallele-specific method.
 18. The method of claim 17, wherein saidallele-specific method is allele-specific probe hybridization,allele-specific primer extension, or allele-specific amplification. 19.The method of claim 18, wherein said method is performed using anallele-specific primer provided in Table
 3. 20. The method of claim 1which is an automated method.
 21. The method of claim 1, furthercomprising correlating the presence of said polymorphism with saidhuman's responsiveness to a therapeutic agent.
 22. The method of claim21, wherein said therapeutic agent comprises an anti-IL12 or anti-IL23antibody. 23-25. (canceled)
 26. A method for reducing risk ofautoinflammatory disease in a human, comprising administering to saidhuman an effective amount of a therapeutic agent, said human having beenidentified as having an increased risk for autoinflammatory disease dueto the presence or absence of a polymorphism selected from the groupconsisting of the polymorphisms as represented by position 101 of anyone of the nucleotide sequences of SEQ ID NOS:219, 21-218, and 220-307or its complement.
 27. The method of claim 26, wherein said methodcomprises testing nucleic acid from said human for the presence orabsence of said polymorphism.
 28. The method of claim 26, wherein saidautoinflammatory disease is psoriasis or Crohn's disease.
 29. (canceled)30. The method of claim 26, wherein said therapeutic agent targets atleast one of IL12 and IL23.
 31. The method of claim 30, wherein saidtherapeutic agent comprises an anti-IL12 or anti-IL23 antibody.
 32. Themethod of claim 31, wherein said therapeutic agent comprises ananti-IL-12p40 antibody selected from the group consisting of ABT-874 andCNTO-1275. 33-38. (canceled)
 39. A kit for determining whether a humanhas an altered risk for autoinflammatory disease, wherein said kitcomprises at least one container and at least one oligonucleotide storedin said container, wherein said oligonucleotide is capable of detectingthe presence or absence of a polymorphism selected from the groupconsisting of the polymorphisms as represented by position 101 of anyone of the nucleotide sequences of SEQ ID NOS:219, 21-218, and 220-307or its complement.
 40. The kit of claim 39, wherein said oligonucleotideselectively hybridizes to said nucleic acid in the presence of saidpolymorphism and does not hybridize to said nucleic acid in the absenceof said polymorphism.
 41. (canceled)